Drake, K. A. | bioRxiv Science

bioRxiv2025

Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about regulation of the stromal progenitor population. Here, we demonstrate that disruption of the NPC lineage via loss of Wt1 (i.e., Six2cre;Wt1c/c) results in an expansion of Foxd1+ stromal progenitor cells. Analyses of the developing stroma in two additional models, including Wnt4-null mutants (which fail to form nephron structures similar to Six2cre;Wt1c/c kidneys) and NPC ablation via diphtheria toxin (i.e., Six2cre;RosaDTAc/+), both phenocopy Six2cre;Wt1c/c mutants, thus further confirming that defects in the NPC lineage result in abnormal development of the stromal progenitor population. Furthermore, we identify a subcluster of the Foxd1+ stroma that appears expanded in the three mutant mouse models and conserved in human fetal kidneys. Overall, the findings from this study suggest that loss of differentiating nephron structures may result in possible over proliferation of the stromal progenitor population and/or a block in stromal differentiation and further highlight how crosstalk amongst the progenitor cell lineages coordinates multiple aspects of kidney development. KEY POINTSO_LIMutant mouse models targeting the nephron lineage (i.e., Six2cre;Wt1c/c and Wnt4-null mutants which fail to form early nephron structures) suggest that a block in NPC differentiation results in an abnormal expansion of the Foxd1+ stromal progenitor population. C_LIO_LIMutant kidneys with NPC ablation (i.e., Six2cre;RosaDTAc/+) show maintenance of stromal progenitors independent of signals from adjacent nephron progenitors and ureteric bud. C_LIO_LISingle nuclei RNA-seq identifies three subclusters of the Foxd1+ stromal progenitor population at E15.5, including one cluster of proliferating cells and a distinct Fap+, Igf1+, Gria1+, Gdnf- subcluster which appears expanded in Six2cre;Wt1c/c, Wnt4-null, and Six2cre;RosaDTAc/+ mutant kidneys and conserved in human fetal kidneys. C_LI

developmental biology↗

bioRxiv2023

Multi-omic Profiling Reveals Early Immunological Indicators for Identifying COVID-19 Progressors

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. One Sentence SummaryImmunological changes associated with COVID-19 progression can be detected during the early stages of infection.

immunology↗