Hofbauer Cell Reduction in GDM: Does a Decreased Quantity Mask a Deeper Immunovascular Dysfunction?

Dear Editor, We carefully reviewed the article by Fakonti et al. regarding changes in the number and phenotype of Hofbauer cells (HBCs) in placentas from pregnancies with gestational diabetes mellitus (GDM) 1. This study demonstrated that GDM is associated with a decrease in HBC abundance in terminal villi without changes in the M2-like phenotype, and a positive correlation between HBC markers and PECAM1/CD31. These findings are important because they reinforce the concept that fetal macrophages play a role in placental vascular homeostasis. However, the quantitative reduction in HBCs likely represents only part of a more complex spectrum of immunovascular dysfunction in GDM. First, the absence of an M1/M2 phenotype shift at the classical marker level does not necessarily rule out functional reprogramming. Recent research suggests that the M1/M2 dichotomy is insufficient to characterise differences among placental macrophages 2. Single-cell studies of first-trimester HBCs have shown that subpopulations exist with distinct transcriptomic profiles associated with angiogenesis and immune control 3. Consequently, GDM may not induce classical M1 polarisation. However, using a limited panel of markers, it may modulate specific HBC subtypes that would otherwise be undetectable. Hidden alterations in metabolic pathways, oxidative responses, or phagocytic capacity may be uncovered through high-resolution transcriptomic analysis or functional proteomic approaches. Second, the hypothesis of a pro-angiogenic role of HBC, previously mentioned 4, is supported by the positive correlation between HBC markers and PECAM1/CD31 in this study 1. However, this correlation is associative and occurs in an immature placenta. Given that villus angiogenesis is most active in the first and middle trimesters, GDM, which is often diagnosed at 24–28 weeks, may disrupt HBC dynamics early, before it becomes clinically apparent. According to the Developmental Origins of Health and Disease (DOHaD) model, intrauterine exposure to hyperglycaemia can program the fetal immune response in the long term 5, 6. Therefore, the decrease in HBC at term may be a cumulative result of early insults that cannot be accurately traced to the end of gestation. Third, further research is needed to examine the immunological impact of HBC reduction on the risk of neonatal infection. HBC can actively ward off viral and bacterial antigens 7, 8. Hyperglycaemia is well known to impair innate immune function and macrophage phagocytosis 9. In the case of GDM, experimental studies assessing the HBC response to TLR stimulation or ex vivo infection would be invaluable. This is because infants born to diabetic mothers are more susceptible to infection. This is because the combination of HBC reduction and possible metabolic dysfunction can contribute to immunological vulnerability in the fetoplacental unit. Fourth, the lack of association between HBC changes and LGA status in this study 1 raises an important question: do HBCs play a role in the quality of vascularisation rather than the quantity of fetal growth? Systematic pathology studies have shown that GDM is associated with changes in vascular architecture and villous maturity 10. The possibility that HBCs modulate nutrient exchange efficiency through interactions with endothelial cells or the extracellular matrix, without directly determining birth weight, needs to be tested using functional approaches, such as HBC–endothelial co-cultures or placental organoid models. Furthermore, we appreciate the authors' methodological approach, which focused on terminal villi analysis and area normalisation to reduce sampling bias. However, to clarify the relationship between hyperglycaemia and HBC dynamics, we could have incorporated clinical data on glycaemic control, insulin therapy, or continuous glucose monitoring, which are known to be associated with fetal outcomes 6. Overall, the study by Fakonti et al. 1 shows that GDM is associated with decreased HBC counts, without changes in the classical M2 phenotype. Moving from quantitative to functional and temporal descriptions of HBC in GDM is the next step in the scientific discussion. Whether HBC reduction is an epiphenomenon or a primary mediator of placental immunovascular dysfunction in gestational diabetes can be answered by multi-omics approaches, longitudinal analyses across trimesters, and in vitro mechanistic studies. This approach is not only relevant to reproductive immunology but also has the potential to bridge understanding of the links between placental inflammation, angiogenesis, and cardio metabolic disease programming in offspring. The authors have nothing to report.