Biology subjects

Ingber, D.

Publications and source records attributed to Ingber, D..

6 recordsLinked to original sources

bioRxiv2026

Neural Activation of Human Primary Intestinal Enteroendocrine L-cells

Intestinal enteroendocrine L-cells play a central role in metabolic homeostasis by secreting the gut hormones GLP-1 and PYY, but whether and how neural signals regulate human L-cell function remains poorly understood. This gap reflects the limited availability of human model systems enriched for mature L-cells. Here, we establish a differentiation strategy that generates human donor-derived ileal organoids with markedly increased L-cell abundance, enabling functional interrogation of L-cell physiology in their basal state. Using this system, we show that cholinergic and adrenergic stimuli activate L-cells, triggering calcium influx and secretion of GLP-1 and PYY. Pharmacological analysis reveals that cholinergic regulation of human L-cells is mediated predominantly through M3 muscarinic receptors, while adrenergic regulation is mediated through the {beta}1 adrenergic receptor. Neurotransmitter-evoked activation also initiates gap junction-dependent calcium waves that propagate across the intestinal epithelium; however, disruption of epithelial coupling by abolishing calcium propagation does not impair hormone secretion. Together, these findings identify L-cells as integrative hubs that couple neural signals to gut hormone secretion and epithelial calcium waves, providing mechanistic insight into the gut-brain axis and how the nervous system regulates intestinal endocrine function in human intestine.

cell biology↗

bioRxiv2024

DNA origami vaccine (DoriVac) nanoparticles improve both humoral and cellular immune responses to infectious diseases

Current SARS-CoV-2 vaccines have demonstrated robust induction of neutralizing antibodies and CD4+ T cell activation, however CD8+ responses are variable, and the duration of immunity and protection against variants are limited. Here we repurposed our DNA origami vaccine nanotechnology, DoriVac, for targeting infectious viruses, namely SARS-CoV-2, HIV, and Ebola. The DNA origami nanoparticle, conjugated with infectious-disease-specific heptad repeat 2 (HR2) peptides, which act as highly conserved antigens, and CpG adjuvant at precise nanoscale spacing, induced neutralizing antibodies, Th1 CD4+ T cells, and CD8+ T cells in naive mice, with significant improvement over a bolus control. Pre-clinical studies using lymph-node-on-a-chip systems validated that DoriVac, when conjugated with antigenic peptides or proteins, induced promising cellular and humoral immune responses in human cells. Moreover, DoriVac bearing full-length SARS-CoV-2 spike protein achieved immune responses comparable to current mRNA vaccine platforms while potentially reducing storage constraints. These results suggest that DoriVac holds potential as a versatile, modular vaccine platform, capable of inducing both humoral and cellular immunities, underscoring its potential utility in addressing future pandemics.

immunology↗

bioRxiv2021

Predicting drug concentrations in PDMS microfluidic organ chips

Microfluidic organ-on-a-chip (Organ Chip) cell culture devices are often fabricated using polydimethylsiloxane (PDMS) because it is biocompatible, transparent, elastomeric, and oxygen permeable; however, hydrophobic small molecules can absorb to PDMS, which makes it challenging to predict drug responses. Here, we describe a combined simulation and experimental approach to predict the spatial and temporal concentration profile of a drug under continuous dosing in a PDMS Organ Chip containing two parallel channels separated by a porous membrane that is lined with cultured cells, without prior knowledge of its log P value. First, a three-dimensional finite element simulation of drug loss into the chip was developed that incorporates absorption, adsorption, convection, and diffusion, which predicts changes in drug levels over time and space as a function of potential PDMS diffusion coefficients and log P values. By then experimentally measuring the diffusivity of the compound in PDMS and determining its partition coefficient through mass spectrometric analysis of the drug concentration in the channel outflow, it is possible to estimate the effective log P range of the compound. The diffusion and partition coefficients were experimentally derived for the antimalarial drug and potential SARS-CoV-2 therapeutic, amodiaquine, and incorporated into the model to quantitatively predict the drug-specific concentration profile over time measured in human Lung Airway Chips lined with bronchial epithelium interfaced with pulmonary microvascular endothelium. The same strategy can be applied to any device geometry, surface treatment, or in vitro microfluidic model to predict the spatial and temporal gradient of a drug in 3D without prior knowledge of the partition coefficient or the rate of diffusion in PDMS. Thus, this approach may expand the use of PDMS Organ Chip devices for various forms of drug testing.

bioengineering↗

bioRxiv2020

Mechanosensation Mediates Long-Range Spatial Decision-Making in an Aneural Organism

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, we reveal that Physarum can use mechanosensation to reliably make decisions about distant objects its environment, preferentially growing in the direction of heavier, substrate-deforming but chemically-inert masses. This long-range mass-sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or addition of a mechanosensitive transient receptor potential channel inhibitor. Computational modeling revealed that Physarum may perform this calculation by sensing the fraction of its growth perimeter that is distorted above a threshold strain - a fundamentally novel method of mechanosensation. Together, these data identify a surprising behavioral preference relying on biomechanical features and not nutritional content, and characterize a new example of an aneural organism that exploits physics to make decisions about growth and form. HighlightsO_LIThe aneural Physarum makes behavioral decisions by control of its morphology C_LIO_LIIt has a preference for larger masses, which it can detect at long range C_LIO_LIThis effect is mediated by mechanosensing, not requiring chemical attractants C_LIO_LIMachine learning reveals that it surveys environment and makes decision in < 4 hours C_LIO_LIA biophysical model reveals how its pulsations enable long-distance mapping of environmental features C_LI

animal behavior and cognition↗

bioRxiv2019

Discovery of influenza drug resistance mutations and host therapeutic targets using a human airway chip

Here we demonstrate that influenza virus replication, host responses to infection, evolution through mutation or gene reassortment, and clinical efficacy of antiviral drugs can be reconstituted in a human Airway Chip microfluidic culture device. Modeling human-to-human transmission of infection in the continued presence of antiviral drugs on chips led to the emergence of clinically prevalent mutations responsible for amantadine- and oseltamivir-resistance, as well as the discovery of new resistance mutations. Analysis of infection responses resulted in identification of host therapeutic targets and demonstration that existing non-antiviral drugs may be repurposed to inhibit viral replication and synergize with antiviral therapeutics by targeting the host response to infection rather than the virus itself. This Influenza Chip may represent an alternative preclinical tool for development of new antiviral drugs and vaccines.\n\nOne Sentence SummaryNew drug resistance mutations and potential tolerance-inducing therapeutics were discovered using an organ chip model of influenza infection.

bioengineering↗

bioRxiv2019

Liver-Chip: Reproducing Human and Cross-Species Toxicities

Nonclinical rodent and non-rodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans contributing to drug failures in the clinic. Here we applied microengineered Organ-on-Chip (Organ-Chip) technology to design rat, dog, and human Liver-Chips containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chips detected diverse phenotypes of liver toxicity including hepatocellular injury, steatosis, cholestasis, and fibrosis as well as species-specific toxicities when treated with tool compounds. Multi-species Liver-Chips may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.\n\nOne Sentence SummaryMicroengineered Organ-Chip technology has been used to design rat, dog and human Liver-Chips that recapitulate species-specific liver toxicities.

pharmacology and toxicology↗