Biology subjects

Fernandez-Maestre, I.

Publications and source records attributed to Fernandez-Maestre, I..

3 recordsLinked to original sources

bioRxiv2026

CAR T cell targeting of inflammatory myeloid progenitors in the bone marrow remodels border-associated macrophages and reverses cognitive aging

Aging is associated with progressive neuroinflammation and cognitive decline, yet the cellular sources that sustain this process and whether they can be targeted peripherally remain unclear. Here, we identify inflammatory border-associated macrophages (BAMs) as key drivers of neuroinflammation in aging and show that their therapeutic and prophylactic elimination through intrathecal CAR T cell therapy restores cognitive performance in mouse models of aging and Alzheimer's disease. Furthermore, targeting of aged inflammatory bone marrow myeloid progenitors through either intravenous CAR T cells, which do not infiltrate the brain, or through transplantation of CAR T-treated progenitors is sufficient to reduce neuroinflammation and cognitive impairment. These findings reveal that bone marrow myeloid progenitors harbor a heritable inflammatory transcriptional state that is transmitted to their BAM progeny, driving neuroinflammation and cognitive deterioration, and conserved in human aging. Critically, this proinflammatory state is marked by the upregulation of surface proteins, enabling precise peripheral CAR T cell targeting of these progenitors for long-lasting therapeutic effects in cognitive aging.

cell biology↗

bioRxiv2024

PURE-seq identifies Egr1 as a Potential Master Regulator in Murine Aging by Sequencing Long-Term Hematopoietic Stem Cells

Single-cell transcriptomics is valuable for uncovering individual cell properties, particularly in highly heterogeneous systems. However, this technique often results in the analysis of many well- characterized cells, increasing costs and diluting rare cell populations. To address this, we developed PURE-seq (PIP-seq for Rare-cell Enrichment and Sequencing) for scalable sequencing of rare cells. PURE-seq allows direct cell loading from FACS into PIP-seq reactions, minimizing handling and reducing cell loss. PURE-seq reliably captures rare cells, with 60 minutes of sorting capturing tens of cells at a rarity of 1 in 1,000,000. Using PURE-seq, we investigated murine long- term hematopoietic stem cells and their transcriptomes in the context of hematopoietic aging, identifying Egr1 as a potential master regulator of hematopoiesis in the aging context. PURE-seq offers an accessible and reliable method for isolating and sequencing cells that are currently too rare to capture successfully with existing methods.

bioengineering↗

bioRxiv2021

Transcription factor induction of vascular blood stem cell niches in vivo

The hematopoietic niche is a supportive microenvironment comprised of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses, we define a conserved gene expression signature and cis-regulatory landscape unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code involving members of the Ets, Sox and Nuclear Hormone Receptor families that is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.

developmental biology↗