Biology subjects

Mosteiro, L.

Publications and source records attributed to Mosteiro, L..

4 recordsLinked to original sources

bioRxiv2026

Hypothalamic oligodendrocytes regulate systemic energy balance through Notch-dependent state transitions

The central mechanisms through which glial cells regulate whole-body metabolism remain poorly understood. Here, we identify Notch signaling in hypothalamic oligodendrocyte lineage cells as a previously unrecognized regulator of systemic energy homeostasis. Pharmacological inhibition of the Notch ligands Jagged1 (Jag1) and Jagged2 (Jag2) induces rapid and reversible weight loss across diverse physiological and metabolic contexts independently of toxicity or caloric intake. Single-nucleus transcriptomic analyses identify hypothalamic oligodendrocyte precursor cells (OPCs) as the principal Notch-responsive population following systemic Jag1/2 inhibition and reveal expansion of a metabolically specialized GPR17 intermediate state characterized by enhanced oxidative metabolism and increased predicted communication with hypothalamic neurons. This glial remodeling is accompanied by fasting-like transcriptional reprogramming of AgRP neurons, reorganization of melanocortin-autonomic circuit activity, and activation of peripheral catabolic programs. Importantly, selective deletion of Notch1/2 in hypothalamic OPCs recapitulates the major physiological and metabolic effects of systemic Jag1/2 inhibition, establishing oligodendrocyte Notch signaling as a causal regulator of whole-body metabolism. Together, our findings establish Notch-dependent oligodendrocyte state transitions as a previously unrecognized mechanism linking glial plasticity to systemic energy homeostasis.

physiology↗

bioRxiv2024

Notch signaling maintains a progenitor-like subclass of hepatocellular carcinoma

Hepatocellular carcinomas (HCCs) constitute one of the few cancer indications for which mortality rates continue to rise. While Notch signaling dictates a key progenitor lineage choice during development, its role in HCC has remained controversial. Using therapeutic antibodies targeting Notch ligands and receptors to screen over 40 patient-derived xenograft models, we here identify progenitor-like HCCs that crucially depend on a tumor-intrinsic JAG1-NOTCH2 signal. Inhibiting this signal induces tumor regressions by triggering progenitor-to-hepatocyte differentiation, the same cell fate-switch that Notch controls during development. Transcriptomic analysis places the responsive tumors within the well-characterized progenitor subclass, a poor prognostic group of highly proliferative tumors, providing a diagnostic method to enrich for Notch-dependent HCCs. Furthermore, single-cell RNA sequencing uncovers a heterogeneous population of tumor cells and reveals how Notch inhibition shifts cells from a mixed cholangiocyte-hepatocyte lineage to one resembling mature hepatocytes. Analyzing the underlying transcriptional programs brings molecular detail to this process by showing that Notch inhibition de-represses expression of CEBPA, which enables the activity of HNF4, a hepatocyte lineage factor that is otherwise quiescent. We thus describe a compelling and targetable dependency in a poor-prognosis class of HCCs.

cancer biology↗

bioRxiv2022

Discovery of thyrocyte heterogeneity reveals an essential role of Notch signaling in thyroid function and mammalian homeostasis

The thyroid functions at the apex of a web of endocrine organs that control cell growth, differentiation and metabolic homeostasis. Thyroid dysregulation significantly impacts human health in myriad ways with thyroid diseases standing as the most common endocrine disorder. Despite the essential role of the thyroid in human health, a high-resolution view of the cellular composition as well as molecular mechanisms that govern function of this crucial organ have been lacking. Employing the first single-cell analyses of adult mouse thyroid, we here report the discovery of unexpected thyrocyte heterogeneity, specifically three distinct thyrocyte subtypes marked by different metabolic and Notch signaling patterns. Using a battery of pharmacologic and genetic methods, we find that selective inhibition of Notch ligands and receptors disrupts thyrocyte mitochondrial activity and ROS production, thus decreasing levels of circulating thyroid hormones, inducing hypothyroidism and disrupting whole-body thermoregulation. We find an enriched frequency of hypothyroidism in children with Alagille Syndrome, a genetic disorder marked by Notch loss-of-function mutations, suggesting that our Notch-thyroid mechanisms are relevant in humans and directly account for Alagille hypothyroidism. Overall, our work reveals that Notch, although classically described as a developmental pathway that determines cell fate, controls homeostasis and thermoregulation in the adult through a mitochondria-based mechanism in a subset of thyrocytes. Our fine-grained picture of the thyroid unveils a novel understanding of this key metabolic organ and provides clinically impactful insights into its pathological dysfunctions.

cell biology↗

bioRxiv2022

Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

cell biology↗