Biology subjects

Rossi, F. M.

Publications and source records attributed to Rossi, F. M..

8 recordsLinked to original sources

bioRxiv2025

Modulation of cofilin 1 phosphorylation induces juvenile-like plasticity in the adult mouse visual cortex.

Cofilin 1 is an actin-depolymerizing protein that plays a fundamental role in actin dynamics, particularly within dendritic spines, where it has been implicated in both structural and functional plasticity. We recently demonstrated (by differential proteomics, western blot and immunohistochemistry) that the expression of cofilin 1 and its inactive phosphorylated form are dynamically regulated in the mouse visual cortex during postnatal development and by visual experience. Moreover, we found that cofilin 1 expression levels correlates with periods of heightened plasticity in the mouse visual cortex. In this study, we analyzed whether the pharmacological modulation of cofilin 1 activity affects plasticity processes in the visual cortex. Adult mice were treated with a synthetic peptide inhibitor of cofilin 1 activity (PCOF) or a control peptide (TAT) and then monocularly deprived of vision during 3 days. Following reopening of the deprived eye, structural plasticity was assessed by quantifying dendritic spine density using Golgi-like staining, and visual plasticity was evaluated by measuring visual acuity through the optomotor response test. Our results show that, in adult mice treated with the PCOF peptide - but not in controls - monocular deprivation led to a significant reduction in dendritic spine density in the contralateral visual cortex, as well as a decrease in visual acuity of the previously deprived eye. These findings indicate that cofilin 1 activity is crucial for the regulation of experience-dependent plasticity in the adult mouse visual cortex.

neuroscience↗

bioRxiv2025

IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas

Introducing Brutons tyrosine kinase (BTK) inhibitors has significantly improved outcomes for patients with B-cell malignancies and autoimmune disorders. However, resistance, either primary or acquired, remains a major clinical challenge. To better understand the underlying resistance mechanisms to BTK inhibitors, we established an ibrutinib-resistant model from a patient-derived splenic marginal zone lymphoma (MZL) cell line (VL51) through prolonged drug exposure. Resistant cells exhibited a 15-fold increase in ibrutinibs IC50, along with distinct morphological changes, mitochondrial activation, and cross-resistance to covalent, non-covalent BTK inhibitors and BTK degraders. Integrated transcriptomic, epigenomic, and proteomic analyses identified overexpression and secretion of IL-16 as a key feature of resistance, driven by chromatin remodeling and activation of the FLI1 transcription factor. IL-16 conferred ibrutinib resistance via CD9-mediated activation of the NF-{kappa}B and AKT signaling pathways and was found to be elevated in the serum of ibrutinib-refractory CLL patients. Functional studies showed that targeting the IL-16/CD9 axis using neutralizing antibodies or CD9-binding peptides restored sensitivity to BTK inhibitors and R-CHOP chemotherapy in MZL, mantle cell lymphoma, and diffuse large B-cell lymphoma models. These findings reveal a novel, targetable resistance mechanism with potential therapeutic implications for overcoming BTK inhibitor resistance in B-cell lymphomas.

cancer biology↗

bioRxiv2023

Sex biased human thymic architecture guides T cell development through spatially defined niches

Within the thymus, regulation of the cellular cross-talk directing T cell development is dependent on spatial interactions within specialized niches. To create a holistic, spatially defined map of tissue niches guiding postnatal T cell development we employed the multidimensional imaging platform CO-detection by indEXing (CODEX), as well as CITE-seq and ATAC-seq. We generated age-matched 4-5-month-old postnatal thymus datasets for male and female donors, and identify significant sex differences in both T cell and thymus biology. We demonstrate a crucial role for JAG ligands in directing thymic-like dendritic cell development, reveal important functions of a novel population of ECM- fibroblasts, and characterize the medullary niches surrounding Hassalls corpuscles. Together, these data represent a unique age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, and provide an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.

immunology↗

bioRxiv2023

ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms

BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead as single agents to long-lasting complete remission is rather limited especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors and that targeted pharmacological interventions can restore sensitivity to the small molecules. We started from a marginal zone lymphoma (MZL) cell line, Karpas-1718, kept under prolonged exposure to the PI3K{delta} inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole exome sequencing, and pharmacological screening which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK and PI3K inhibitors in parental cells but also in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were shown to be expressed in clinical samples, further extending the findings of the study. In conclusions, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors and treatments that appear to overcome it. Key pointsO_LIA mechanism of secondary resistance to the PI3K{delta} and BTK inhibitors in B cell neoplasms driven by secreted factors. C_LIO_LIResistance can be reverted by targeting ERBB signaling. C_LI

cancer biology↗

bioRxiv2022

Spatial compartmentalization of signalling imparts source-specific functions on secreted factors

Efficient regeneration requires multiple cell types acting in a coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profiled the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. A time-resolved computational model of interactions was generated, and VEGFA-driven endothelial engagement was identified as a key differentiating feature in models of successful and failed regeneration. In addition, it revealed that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we deleted VEGFA from two cell types residing in close proximity, stromal and myogenic progenitors. By comparing responses to different types of damage, we found that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks. HighlightsO_LILigand-receptor signaling redundancy during skeletal muscle regeneration C_LIO_LIInflammatory cells, and muscle and fibro/adipogenic progenitors produce VEGFA C_LIO_LIVEGFA from muscle progenitors control their proliferation after muscle damage C_LIO_LIVEGFA from FAP controls angiogenesis only after ischemic damage C_LI eTOC blurbGroppa et al. performed a novel time-resolved bioinformatics analysis that revealed extensive ligand-receptor redundancy among the cell types contributing to skeletal muscle regeneration. They focused on one of these pathways, and showed that VEGFA from different cell types has distinct roles in regeneration.

cell biology↗

bioRxiv2021

After migration into blood circulation, hematopoietic stem cells can stably self-renew and maintain bone marrow while being skewed toward myeloid lineage when submitted to serial transplantation.

Hematopoietic stem cells (HSCs) mainly reside in bone marrow (BM) within niches providing an appropriate environment for their survival and self-renewal. Although, small numbers of HSCs can quit their residing environment to migrate into blood circulation and re-engraft elsewhere in BM. Mobilizing agents such as granulocyte colony stimulating factor (G-CSF) can amplify this process by inducing massive HSC mobilization into blood circulation. This method is widely used in clinics to treat hematological disorders. However, in physiological conditions, the properties of HSCs after migration (called migratory HSCs) remain incompletely characterized. In this study, we investigated the capacity of migratory HSCs to self-renew, reconstitute and maintain BM. We show that after migration, HSCs can stably self-renew and maintain BM in homeostasis. However, while stably repopulating BM of irradiated recipients, migratory HSCs show a defect in lymphoid lineage reconstitution when subjected to serial transplantations. Our findings provide interesting knowledge on HSC properties after migration, which may benefits therapeutic research on HSC-based therapies to treat hematological disorders.

cell biology↗

bioRxiv2021

The parathyroid hormone-dependent activation of osteoblasts enhances hematopoietic stem cell migration and reduces their engraftment abilities

Hematopoietic stem cells (HSCs) in the bone marrow (BM) reside in HSC niches ensuring their maintenance. The HSC niche is made up of perivascular and trabecular cells including osteoblasts whose role on HSCs remains to be clearly defined. Increased numbers of osteoblasts have been observed in the CL2 transgenic mouse expressing a constitutively activated form of the parathyroid hormone (PTH)/PTH-related peptide receptor. This mouse model mimicking PTH anabolic effect has also been described to exhibit increased numbers of the BM stem/progenitor population. Furthermore, PTH is known to induce BM stem/progenitor cell migration into blood circulation. However PTH role on long-term repopulating HSCs (LT-HSCs) is incompletely known. Here we show that CL2 BM contains a regular proportion of LT-HSCs, suggesting that osteoblasts may not be a determinant of LT-HSC numbers but act mainly on more mature progenitors. We further show increased LT-HSC migration in CL2 mice correlated with higher granulocyte colony-stimulating factor (G-CSF) serum levels, supporting the idea that PTH can enhance the migration of LT-HSCs. Finally, we found a defect in the ability of CL2 BM HSCs to reconstitute irradiated BM suggesting that PTH activation of osteoblasts negatively influences abilities of HSC population to engraft and reconstitute irradiated BM. In summary, our study highlights new insights into the role of the PTH-dependent activation of osteoblasts on LT-HSC migration and their BM repopulation abilities. Our findings will be useful to improve treatments on hematological disorders, especially therapies involving HSC harvest and transplantation.

cell biology↗

bioRxiv2020

Extracellular TGF-β downregulates the expression of Wnt transcription factor TCF7L2/TCF4 in mesenchymal stromal cells and fibroblasts

Mesenchymal stromal/stem cells (MSCs) are multipotent progenitors essential ororganogenesis, tissue homeostasis, regeneration, and scar formation. Tissue injury upregulates TGF-{beta} signaling, which modulates myofibroblast fate, extracellular matrix remodeling, and fibrosis. However, the molecular determinants of MSCs differentiation and survival remain poorly understood. The canonical Wnt Tcf/Lef transcription factors regulate development and stemness, but the mechanisms by which injury-induced cues modulate their expression remain underexplored. Here, we studied the cell-specific gene expression of Tcf/Lef and, more specifically, we investigated whether damage-induced TGF-{beta} impairs the expression and function of TCF7L2, using several models of MSCs, including skeletal muscle fibro-adipogenic progenitors. We show that Tcf/Lefs are differentially expressed and that TGF-{beta} reduces the expression of TCF7L2 in MSCs but not in myoblasts. We also found that the ubiquitin-proteasome system regulates TCF7L2 proteostasis and participates in TGF-{beta}-mediated TCF7L2 protein downregulation. Finally, we show that TGF-{beta} requires HDACs activity to repress the expression of TCF7L2. Thus, our work found a novel interplay between TGF-{beta} and Wnt canonical signaling cascades in PDGFR+ fibroblasts and suggests that this mechanism could be targeted in tissue repa ir and regeneration. Summary statementTGF-{beta} signaling suppresses the expression of the Wnt transcription factor TCF7L2 and compromises TCF7L2-dependent functions in tissue-resident PDGFR+ fibroblasts.

cell biology↗