Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Fetal HSPCs

• Pregnancy

• Emergency myelopoiesis

Main Findings

Neonates are highly susceptible to infections, with a limited capacity of the myeloid progenitors to meet demand and neutropenia being a well-recognized feature of the neonatal immune response. Whether fetal hematopoietic stem and progenitor cells (HSPCs) are phenotypically and functionally distinct from the adult counterparts is not well known. In this preprint Collins et al. characterize the functionality of the late fetal HSPCs. They reveal the conserved hierarchy of the stem cell niche across development (fetal to neonatal to adult), and molecular resemblance of the fetal and neonatal HSPCs to their adult counterparts. Despite these described similarities, as well as the capability of the fetal HSPCs to respond to classical inflammatory stimuli in vitro, they showed only a limited myeloid output at steady state in vivo, compared to the adult counterparts. Furthermore, it was observed, that fetal HSPCs could sense inflammatory signals in utero (upon maternal inflammation), however they failed to activate classical emergency myelopoiesis pathways and were therefore incapable to engage emergency myelopoisis. Exploring the possible factors that may have had a restricting effect on the fetal HSPCs, Collins et al. revealed, that maternal IL-10, naturally evolved to protect and maintain late pregnancy, limits the activation capacity of fetal HSPCs in response to inflammation.

Limitations

• The information on the duration of the restricting effects of IL-10 on the HSPCs in the postnatal period is deficient. The authors mention the importance of the study for understanding the underlying causes of postnatal neutropenia and sepsis, hence the postnatal characterisation of the HSPCs is essential. Suggestion: authors can use the same experimental set-up, but perform analysis at several postnatal time-points instead of fetal to see, when the maternal IL-10 effect disappear and HSPCs acquire a phenotype close to the adult counterparts.

• The mechanism of the IL-10 effect is missing. Increased responsiveness of fetal HSPCs (f.e. increased IL-10R expression), effect of the niche microenvironment (fetal liver vs bone marrow) could be potential contributing factors that impact the phenotype of the HSPCs. Suggestion: 1) In the last part of the paper authors mention, that there was no difference in the LPS response between IL-10+/- and IL-10-/- fetuses carried by IL-10-/+ dams. Measuring IL-10 levels in those fetuses will provide information on whether maternal IL-10 can cross placental berrier and directly act on the fetal HSPCs or whether its effect is indirect. 2) scRNA-seq and bulk RNA-seq were performed on steady-state fetal and adult HSPCs, however the main focus in the paper is on the transcriptional similarities between them. Investigating the differences between the two counterparts (differentially expressed genes, cell trajectory etc.) might be a good starting point.

• Pro-inflammatory cytokines (TNFα, type I IFN, IL-1) are shown to deplete fetal HSPCs and the maternal dificiency of those cytokines prevented the loss. It is not clear, how this finding correlates with the mechanism of the IL-10 restriction. Suggestion: measure IL-10 levels in the plasma of TNFα-/-, Ifnar-/-, Il1r1-/- dams and their fetuses to determine whether pro-inflammarory cytokines have an impact on IL-10 levels.

• The description of an LPS challenge in the paper can be misleading. It is stated, that the model of LPS injections of pregnant dams is a method of inducing an in vivo inflammation, however there is no direct LPS sensing by the fetus, as shown e.g. in Figure 6C (no increase in fetal serum cytokines upon LPS challenge). Suggestion: the authors should specify, that LPS stimulation during pregnancy mimics an in utero exposure to increased levels of maternal pro-inflammatory cytokines upon maternal immune activation (MIA) as during an infection (Meyer et al. Neurosci Biobehav Rev 2009), but this effect is indirect.

Significance/Novelty

How maternal factors affect prenatal development of the immune system is a poorly studied field, however the importance of the topic has recently been recognized as highly essential by the scientific community with an increasing number of studies being published. For instance, some recent studies revealed a long-lasting effect of maternal inflammation on the hematopoietic stem cell compartment with a biased lineage output remaining till the adulthood (Lopez et al. Cell Rep 2022; Lopez et al. Embo J 2023, Mandel et al. Brain Behav Immun 2013). Collins et at. perform a precise characterization of fetal HSPCs on different levels (transcriptional, chromatin, functional), which is essential for a deeper understanding of the hematopoietic system development in general. They also determine, that maternal factors are detrimental in shaping the phenotype of fetal HSPCs and their output, with IL-10 restricting properties being the main highlight of the paper. In summary, despite several limitations (as described above), this study significantly advances our understanding of the fetal hematopoiesis and leaves some open question that are yet to be addressed in the future.

Credit

Reviewed by Emilie Fisher & Alina Fokina as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Medical University of Vienna and other life science institutes in Vienna.

The authors declare no conflict of interests in relation to their involvement in the review.