Browsing by Author "Calero, Macarena"
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Item Erythroid SLC7A5/SLC3A2 amino acid carrier controls red blood cell size and maturation.(iScience, 2023) Bouthelier, Antonio; Fernández-Arroyo, Lucía; Mesa-Ciller, Claudia; Cibrian, Danay; Martín-Cófreces, Noa Beatriz; Castillo-González, Raquel; Calero, Macarena; Herráez Aguilar, Diego; Guajardo-Grence, Andrea; Pacheco, Ana María; Marcos-Jiménez, Ana; Quiroga, Borja; Morado, Marta; Monroy, Francisco; Muñoz-Calleja, Cecilia; Sánchez-Madrid, Francisco; Urrutia, Andrés A.; Aragonés, JuliánInhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5-deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.Item Lipid nanoparticles for antisense oligonucleotide gene interference into brain border-associated macrophages.(Frontiers in Molecular Biosciences, 2022) Calero, Macarena; Moleiro, Lara H.; Sayd, Aline; Dorca, Yeray; Miquel-Rio, Lluis; Paz, Verónica; Robledo-Montaña, Javier; Enciso, Eduardo; Acción, Fernando; Herráez Aguilar, Diego; Hellweg, Thomas; Sánchez, Luis; Bortolozzi, Analía; Leza, Juan C.; García-Bueno, Borja; Monroy, FranciscoA colloidal synthesis’ proof-of-concept based on the Bligh–Dyer emulsion inversion method was designed for integrating into lipid nanoparticles (LNPs) cell-permeating DNA antisense oligonucleotides (ASOs), also known as GapmeRs (GRs), for mRNA interference. The GR@LNPs were formulated to target brain border-associated macrophages (BAMs) as a central nervous system (CNS) therapy platform for silencing neuroinflammation-related genes. We specifically aim at inhibiting the expression of the gene encoding for lipocalin-type prostaglandin D synthase (L-PGDS), an anti-inflammatory enzyme expressed in BAMs, whose level of expression is altered in neuropsychopathologies such as depression and schizophrenia. The GR@LNPs are expected to demonstrate a bio-orthogonal genetic activity reacting with L-PGDS gene transcripts inside the living system without interfering with other genetic or biochemical circuitries. To facilitate selective BAM phagocytosis and avoid subsidiary absorption by other cells, they were functionalized with a mannosylated lipid as a specific MAN ligand for the mannose receptor presented by the macrophage surface. The GR@LNPs showed a high GR-packing density in a compact multilamellar configuration as structurally characterized by light scattering, zeta potential, and transmission electronic microscopy. As a preliminary biological evaluation of the mannosylated GR@LNP nanovectors into specifically targeted BAMs, we detected in vivo gene interference after brain delivery by intracerebroventricular injection (ICV) in Wistar rats subjected to gene therapy protocol. The results pave the way towards novel gene therapy platforms for advanced treatment of neuroinflammation-related pathologies with ASO@LNP nanovectors.