Biology subjects

Mastrogiovanni, M.

Publications and source records attributed to Mastrogiovanni, M..

4 recordsLinked to original sources

bioRxiv2026

Embryonic TGF-β signaling imposes persistent changes to HSPC clonality and inflammatory landscape

Embryonic hematopoiesis is essential for establishing lifelong blood and immune system function. During development, hematopoietic stem and progenitor cells (HSPCs) acquire intrinsic programs that persist into adulthood and can influence disease susceptibility, yet the molecular signals governing these early-life decisions remain poorly understood. Here, we investigated the role of developmental Transforming Growth Factor-{beta} (TGF-{beta}) signaling in regulating HSPC lineage bias and long-term hematopoietic outcomes. Using the zebrafish model, we found that transient embryonic TGF-{beta} signaling inhibition during the HSPC specification window altered their frequency and migration after emergence from the hemogenic endothelium and movement into the key secondary maturation and expansion niche. Single-cell transcriptomic analysis of embryonic HSPCs revealed repression of migration- and cytoskeleton-associated genes alongside dampened expression of myeloid/macrophage-related genes following ALK5 inhibition. Functionally, early ALK5 blockade reduced macrophage numbers and promoted an M2-like immunosuppressive transcriptional profile. These developmental perturbations produced sustained effects on hematopoietic and immune function into adulthood, including diminished inflammatory gene expression, reduced clonal complexity, and impaired regenerative capacity. Together, our findings identify embryonic TGF-{beta} signaling as a key developmental regulator of HSPC fate and immune programming, with potential implications for immune dysfunction and susceptibility to inflammatory-related disease later in life. PAPER HIGHLIGHTS- Transient developmental signaling perturbations reshape hematopoietic trajectories - Embryogenic TGF-{beta} signaling instructs HSPC lineage priming and macrophage specialization - Early HSPC programming establishes persistent inflammatory states, clonal diversity, and modifies regenerative capacity

developmental biology↗

bioRxiv2026

Tracing the Path from 4-Hydroxyphenylpyruvate to the Benzoquinone Ring of Q6 and the p-aminobenzoate pathway in Yeast

AbstractCoenzyme Q (ubiquinone, CoQ) is an essential component of the mitochondrial electron transport chain and a major lipid antioxidant in eukaryotic cells. Formation of its benzoquinone ring requires aromatic precursors whose metabolic origin remains incompletely defined. Here, we elucidate the biochemical link between tyrosine metabolism and the synthesis of the benzoquinone head group of coenzyme Q6 (Q6) in Saccharomyces cerevisiae through the 4-hydroxymandelate (4HMA) pathway. Using isotopic tracing with 13C6-tyrosine, 13C6-4-hydroxybenzoate, and 13C6-p-aminobenzoate (pABA), we demonstrate that tyrosine-derived 4-hydroxyphenylpyruvate is converted into 4-hydroxybenzaldehyde via benzoylformate decarboxylation, defining a functional 4HMA pathway in yeast. Chemical inhibition of benzoylformate decarboxylase with methylbenzoylphosphonate led to accumulation of pathway intermediates, which were identified by GCMS. Consistently, mutants lacking ARO10, DLD1, or DLD2 exhibited strongly decreased 4-hydroxybenzaldehyde formation. Despite disruption of the 4HMA pathway, the pABA route from chorismate compensated, demonstrating S. cerevisiaes metabolic flexibility to use pABA or 4-HB and maintain Q6 ring biosynthesis. Our results provide a mechanistic framework linking aromatic amino acid metabolism to respiratory quinone biosynthesis in eukaryotes and support the evolutionary conservation of the 4HMA-derived pathway as a source of 4-hydroxybenzoate for Q synthesis in higher organisms. O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/734323v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@79d684org.highwire.dtl.DTLVardef@f2a7a4org.highwire.dtl.DTLVardef@dc3f0borg.highwire.dtl.DTLVardef@1af14a6_HPS_FORMAT_FIGEXP M_FIG Graphical abstract.4-hydroxyphenylpyruvic acid (4HPP), 4-hydroxymandelate (4HMA), 4-hydroxybenzoic acid (4HB), p-aminobenzoic acid (pABA). C_FIG

biochemistry↗

bioRxiv2023

Cancer-on-a-chip model shows that the adenomatous polyposis coli mutation impairs T cell engagement and killing of cancer spheroids

Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells is crucial, for instance to predict the efficiency of cell therapy in personalized medicine. However, the destruction of a tumor by CTLs involves CTL migration in the extra-tumoral environment, accumulation on the tumor, antigen recognition, and cooperation in killing the cancer cells. Therefore, identifying the limiting steps in this complex process requires spatio-temporal measurements of different cellular events over long periods. Here, we use a cancer-on-a-chip platform to evaluate the impact of adenomatous polyposis coli (APC) mutation on CTL migration and cytotoxicity against 3D tumor spheroids. The APC mutated CTLs are found to have a reduced ability to destroy tumor spheroids compared with control cells, even though APC mutants migrate in the extra-tumoral space and accumulate on the spheroids as efficiently as control cells. Once in contact with the tumor however, mutated CTLs display reduced engagement with the cancer cells, as measured by a new metric that distinguishes different modes of CTL migration. Realigning the CTL trajectories around localized killing cascades reveals that all CTLs transition to high engagement in the two hours preceding the cascades, which confirms that the low engagement is the cause of reduced cytotoxicity. Beyond the study of APC mutations, this platform offers a robust way to compare cytotoxic cell efficiency of even closely related cell types, by relying on a multiscale cytometry approach to disentangle complex interactions and to identify the steps that limit the tumor destruction.

bioengineering↗

bioRxiv2019

Nitro-fatty acids formation in Virgin Olive Oil during gastric digestion and its relationship to cultivar and fruit ripening

Virgin olive oil (VOO) represents the main source of unsaturated lipids in the Mediterranean diet associated with low mortality. Health benefits of VOO rely on its composition, mainly fatty acids and minor components such as polyphenols. In addition, VOO contains nitro-fatty acids (NO2-FA), novel signaling mediators exhibiting pleiotropic anti-inflammatory responses. Previous work from our group reported the presence of nitro-oleic acid (NO2-OA), nitro-linoleic acid (NO2-LA) and nitro-conjugated linoleic acid (NO2-cLA) in extra virgin olive oil under gastric conditions. Herein, we analyzed the fatty acid profile, phenol, pigment and NO2-FA formation in two contrasting Uruguayan olive cultivars, Arbequina and Coratina at two ripening conditions. We demonstrate that VOO fatty acid nitration is dependent on olive cultivar as well as fruit ripening. Under gastric nitration conditions, the presence of polyphenols in Arbequina VOO promoted fatty acid nitration. In contrast, the absence of polyphenols favor lipid oxidation, decreasing fatty acid nitration. In Coratina, where the content of polyphenolic compounds is higher than in Arbequina, their absence did not affect the formation of NO2-FA. Coratina contains other bioactive constituents such as pigments that could play an important role in protection of VOO from lipid oxidation. Overall, we postulate that unsaponifiable constituents of VOO, e.g. polyphenols and pigments, contribute to the formation of NO2-FA in gastric conditions, thus potentiating their health beneficial

plant biology↗