Biology subjects

Conforti, F.

Publications and source records attributed to Conforti, F..

3 recordsLinked to original sources

bioRxiv2024

Mosaic midbrain organoids: a new tool to study Progressive Supranuclear Palsy and advancing clinical neurology research

Progressive supranuclear palsy (PSP) is a severe neurodegenerative disease pathologically characterized by intracellular tangles of hyperphosphorylated tau protein, widely distributed across the neocortex, basal ganglia, and midbrain. Developing effective drugs for PSP presents challenges due to its complex underpinning mechanism and the absence of robust human models that accurately recapitulate biochemical and pathological features of the disease phenotype. Brain organoids have recently emerged as a three-dimensional tissue culture platform to study brain development and pathology. Here, we present a novel induced pluripotent stem cell (iPSC)-derived mosaic midbrain organoid (mMOs) system from four patients with progressive supranuclear palsy-Richardson syndrome (PSP-RS), aimed at reproducing key molecular disease features while reducing variability across organoids derived from different iPSC donors. The PSP-RS 3D model exhibited accumulation of hyperphosphorylated tau protein, predominance of 4R-tau, increased GFAP-positive cells, and PSP-associated histological alterations compared to organoids derived from healthy donors. Pathologically, diseased mMOs showed typical neurofibrillary tangles and tufted-shaped astrocytes, and poorly branched processes of Tyrosine Hydroxylase-immunoreactive cells with thin terminal branches. Our results suggest that mMOs represent a valuable experimental model for PSP research and hold great promise for future identification of new therapeutic targets for progressive supranuclear palsy. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/597136v1_unfig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@8b2942org.highwire.dtl.DTLVardef@41e3baorg.highwire.dtl.DTLVardef@1cddaeeorg.highwire.dtl.DTLVardef@1e0716c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGF{beta} increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting bone-type cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis.

cell biology↗

bioRxiv2020

A novel isoform of ACE2 is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in the airways for SARS-CoV-2. ACE2 binding to SARS-CoV-2 protein Spike triggers viral fusion with the cell membrane, resulting in viral RNA genome delivery into the host. Despite ACE2s critical role in SARS-CoV-2 infection, an understanding of ACE2 expression, including in response to viral infection, remains unclear. Until now ACE2 was thought to encode five transcripts and one 805 amino acid protein. Here we identify a novel short isoform of ACE2. Short ACE2 is expressed in the airway epithelium, the main site of SARS-CoV-2 infection; it is substantially upregulated in response to interferon stimulation and RV infection, but not in response to SARS-CoV-2 infection, and it shows differential regulation in asthma patients. This short isoform lacks SARS-CoV-2 spike glycoprotein high-affinity binding sites and altogether, our data are consistent with a model where short ACE2 may influence host susceptibility to SARS-CoV-2 infection.

molecular biology↗