Biology subjects

Alvarez-Dominguez, J. R.

Publications and source records attributed to Alvarez-Dominguez, J. R..

6 recordsLinked to original sources

bioRxiv2025

Agentic Lab: An Agentic-physical AI system for cell and organoid experimentation and manufacturing

Reproducibility in biological research and manufacturing remains constrained by the complexity of multi-step protocols, fragmented data-analysis pipelines, and the intrinsic variability of experimental execution. Here, we present Agentic Lab, an agentic-physical AI platform that unifies large language model and vision language model (LLMs/VLMs)-driven reasoning with real-world laboratory operations. Agentic Lab uses multi-agent orchestration architecture, comprising of specialized subagents for knowledge retrieval, protocol design, multimodal data analysis, and training-free segmentation and representation learning for intrinsically explainable single-cell and organoid phenotyping. These agents operate under the orchestration of a virtual principal investigator MolAgent that is linked to an augmented reality (AR)-based physical AI interface, which can bridge digital reasoning with human physical execution. Agentic Lab perceives real-world experimental activities, provides context-aware instructions, identifying procedural errors in real time for humans to correct, and continuously evolves with its long-term memory database expanding through the accumulation of experimental data logs from human scientists. This interaction allows scientists and AI agents to collaborate and co-evolve dynamically, closing the loop between planning, action, and analysis in the traditional cell and organoid research lifecycle. We demonstrate Agentic Lab in organoid differentiation from human pluripotent stem cells, where it autonomously generates protocols, monitors culture procedures, and identifies subtle morphological heterogeneity linked to growth conditions. The system interprets these phenotypes, grounds them in literature, and proposes targeted instructions for improving differentiation efficiency. By combining multi-agent reasoning with physical laboratory awareness, Agentic Lab transforms experimentation and biomanufacturing from a static workflow into an adaptive, feedback-driven, bidirectional process that integrates agentic AI into the research lifecycle. This framework establishes a foundation for intelligent laboratories that integrate design, execution, and interpretation within a unified agentic-physical system.

bioengineering↗

bioRxiv2025

DEC1 Regulates Human β Cell Functional Maturation and Circadian Rhythm

Stem cell-derived islet (SC-islet) organoids offer hope for cell replacement therapy in diabetes, but their immature function remains a challenge. Mature islet function requires the {beta}-cell circadian clock, yet how the clock regulates maturation is unclear. Here, we show that a circadian transcription factor specific to maturing SC-{beta} cells, DEC1, regulates insulin responsiveness to glucose. SC-islet organoids form normally from DEC1-ablated human pluripotent stem cells, but their insulin release capacity and glucose threshold fail to increase during in vitro culture and upon transplant. This deficit reflects downregulation of maturity-linked effectors of glucose utilization and insulin exocytosis, blunting glycolytic and oxidative metabolism, and is rescued by increasing metabolic flux. Moreover, DEC1 is needed to boost SC-islet maturity by synchronizing circadian glucose-responsive insulin secretion rhythms and clock machinery. Thus, DEC1 links circadian rhythms to human {beta}-cell maturation, highlighting the essential role of circadian control in generating fully functional SC-islet organoids.

developmental biology↗

bioRxiv2024

Cyborg islets: implanted flexible electronics reveal principles of human islet electrical maturation

Flexible electronics implanted during tissue formation enable chronic studies of tissue-wide electrophysiology. Here, we integrate tissue-like stretchable electronics during organogenesis of human stem cell-derived pancreatic islets, stably tracing single-cell extracellular spike bursting dynamics over months of functional maturation. Adapting spike sorting methods from neural studies reveals maturation-dependent electrical patterns of and {beta}-like (SC- and {beta}) cells, and their stimulus-coupled dynamics. We identified two major electrical states for both SC- and {beta} cells, distinguished by their glucose threshold for action potential firing. We find that improved hormone stimulation capacity during extended culture reflects increasing numbers of SC-/{beta} cells in low basal firing states, linked to energy and hormone metabolism gene upregulation. Continuous recording during further maturation by entrainment to daily feeding cycles reveals that circadian islet-level hormone secretion rhythms reflect sustained and coordinate oscillation of cell-level SC- and {beta} electrical activities. We find that this correlates with cell-cell communication and exocytic network induction, indicating a role for circadian rhythms in coordinating system-level stimulus-coupled responses. Cyborg islets thus reveal principles of electrical maturation that will be useful to build fully functional in vitro islets for research and therapeutic applications.

bioengineering↗

bioRxiv2023

An adult clock component links circadian rhythms to pancreatic β-cell maturation

Circadian clocks attune metabolism to daily energy cycles, but how they regulate functional maturation of metabolic tissues is poorly understood. Here we show that DEC1, a clock transcription factor induced in adult islet {beta} cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds and regulates maturity-linked genes to integrate insulin exocytosis with {beta}-cell energy metabolism, and {beta}-cell-specific Dec1 ablation disrupts their transcription synchrony. Dec1-disrupted mice develop lifelong glucose intolerance and insulin deficiency, despite normal islet formation. Metabolic dysfunction upon {beta}-cell Dec1 loss stems from poor coupling of islet insulin secretion to glucose metabolism, reminiscent of fetal/neonatal islet immaturity. We link stunted maturation to a deficit in circadian bioenergetics, prompted by compromised glucose utilization, mitochondrial dynamics, and respiratory metabolism, which is rescued by increased metabolic flux. Thus, DEC1 links circadian clockwork to {beta}-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization.

cell biology↗

bioRxiv2020

An adipocyte-specific lncRAP2 - Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs

lncRAP2 is a conserved cytoplasmic adipocyte-specific lncRNA required for adipogenesis. Using hybridization-based purification combined with in vivo interactome analyses, we show that lncRAP2 forms ribonucleoprotein complexes with several mRNA stability and translation modulators, among them Igf2bp2. Transcriptome-wide identification of Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic effectors and regulators. Depleting either lncRAP2 or Igf2bp coordinately downregulates these same target proteins. Ribosome profiling and quantitative proteomics show that this occurs predominantly at the level of mRNA, as binding of the lncRAP2-Igf2bp complex does not affect mRNA translation. Suppressing lncRAP2 or Igf2bp2 selectively destabilizes many mRNAs encoding proteins essential for energy expenditure, including Adiponectin, reducing adipocyte lipolytic capacity. Genome-wide association studies reveal specific association of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and we find that adipose lncRAP2 and Igf2bp2 are suppressed during obesity and diabetes progression. Thus, the lncRAP2-Igf2bp complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.

cell biology↗

bioRxiv2019

Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling

Investigating pancreatic islet differentiation from human stem cells in vitro provides a unique opportunity to dissect mechanisms that operate during human development in utero. We developed methods to profile DNA methylation, chromatin accessibility, and histone modifications from pluripotent stem cells to mature pancreatic islet cells, uncovering widespread epigenome remodeling upon endocrine commitment. Key lineage-defining loci are epigenetically primed before activation, foreshadowing cell fate commitment, and we show that priming of -cell-specific enhancers steers polyhormonal cells toward an -cell fate. We further dissect pioneer factors and core regulatory circuits across islet cell differentiation and maturation stages, which identify LMX1B as a key regulator of in vitro-derived endocrine progenitors. Finally, by contrasting maturing stem cell-derived to natural {beta}-cells, we discover that circadian metabolic cycles trigger rhythmic control of insulin synthesis and release and promote mature insulin responsiveness via an increased glucose threshold. These findings form a basis for understanding mechanisms orchestrating human islet cell specification and maturation.

genomics↗