Biology subjects

Schipani, E.

Publications and source records attributed to Schipani, E..

3 recordsLinked to original sources

bioRxiv2025

HIF1α controls somitogenesis and spine development by regulating levels of intracellular oxygen in the presomitic mesoderm

Embryonic axis extension depends on presomitic mesoderm (PSM) segmentation into somites, which give rise to vertebrae and muscles. The PSM is a highly glycolytic structure. HIF1 is a transcription factor that regulates bioenergetic metabolism by promoting glycolysis and suppressing mitochondrial respiration. Conditional deletion of HIF1 in the PSM resulted in vertebral malformations, including shortened, misshapen vertebrae and additional thoracic segments. These defects correlated with disrupted segmentation clock oscillations, marked by abnormal Hes7 and Lfng expression. HIF1 loss also induced intracellular hypoxia, likely due to increased mitochondrial respiration. Hyperoxic exposure of mutant embryos corrected hypoxia, restoring Hes7 oscillations and somitogenesis. These findings highlight HIF1s essential role in ensuring proper segmentation clock function and somitogenesis by maintaining intracellular oxygen homeostasis through reprogramming of metabolism.

developmental biology↗

bioRxiv2025

Local erythropoiesis directs oxygen availability in bone fracture repair

Oxygen tension dynamically regulates stem cell fate and tissue regeneration, yet how local oxygen availability is controlled within the bone marrow niche remains poorly understood. While bone marrow injury, such as by bone fracture, disrupts marrow vasculature, the consequences on local oxygen tension remain unclear. Here, we show in mice that while the tissue oxygen tension in bone marrow is low (25 mmHg, [~]4% O2), intracellular oxygenation is heterogeneous and erythroid cells are high in oxygen. Bone fracture elevates oxygen tension in the injured bone marrow (>55 mmHg, [~]8%), which persists for over a week post-injury. This oxygen elevation results not from angiogenesis, but rather from localized expansion of erythroid precursor cells in the injured bone marrow. The activated erythroid precursors synthesize hemoglobin and accumulate oxygen, acting as local modulators of oxygen tension. Blocking transferrin receptor 1 (CD71)-mediated iron uptake impairs hemoglobin synthesis, reduces local oxygen levels, and enhances bone regeneration through increased angiogenesis and osteogenesis. These findings identify erythroid precursors as active regulators of local oxygen availability in the bone marrow niche, which may be targetable to enhance tissue regeneration.

cell biology↗

bioRxiv2021

Macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization

Clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment of a cellular response to hypoxia. Here we show that efferocytic macrophages promote HIF-1 stabilization under normoxic conditions through interaction with phosphorylated STAT3. Inflammatory cytokine gene expression analysis of efferocytic HIF-1-mutant macrophages revealed a reduced expression of the pro-tumorigenic Mif. Furthermore, stabilization of HIF-1 using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in macrophages. Finally, macrophages treated with recombinant MIF protein activated NF-{kappa}B (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by tumor-associated macrophages triggers p-STAT3/HIF-1/MIF signaling to enhance tumor-promoting inflammation in bone, suggesting this axis as a target for metastatic prostate cancer.

cancer biology↗