Biology subjects

Lieberman, L. A.

Publications and source records attributed to Lieberman, L. A..

3 recordsLinked to original sources

bioRxiv2025

Personalized Gut-Liver Microphysiological System Maps Donor-Specific Tissue Resident Immunity and Reveals a Conserved Metabolic Crosstalk

Tissue-resident immune (TRI) niches are unique to tissues and greatly vary between individuals. We built a personalized gut-liver microphysiological system (MPS) to recapitulate these profiles, combining primary colon epithelium, hepatocytes, and autologous CD45 TRI cells of two donors. Single-cell RNA-seq of colon and liver revealed distinct TRI profiles and predicted responses distinct between donors. Co-culture established organ and donor-specific immune programs: colonic epithelium induced Th1/Th17 polarization in Donor 1 but B cell differentiation in Donor 2. Gut-liver crosstalk in all donors converged on a retinoid-bile acid metabolic axis with a muted inflammatory set-point, indicating that circulating metabolites can override baseline immune differences. Microbial agonist challenges of gut compartments revealed distinct liver responses: Poly(I:C) induced a uniform type-I/III interferon burst, LPS triggered a stronger response in Donor 1, and 5-OP-RU selectively activated Donor 2. Our personalized, immune-competent gut-liver MPS demonstrates that a conserved metabolic dialogue coexists with and is modulated by TRI profiles. This work provides a blueprint for exploring immunometabolic diseases and precision therapeutics in multi-organ models reflecting human immune diversity.

bioengineering↗

bioRxiv2022

Development of a high-throughput barrier function assay using primary human gut organoids

Disruptions in the gut epithelial barrier can lead to the development of chronic indications such as inflammatory bowel disease (IBD). Historically, barrier function has been assessed in cancer cell lines, which do not contain all human intestinal cell types, leading to poor translatability. To bridge this gap, we adapted human primary gut organoids grown as monolayers to assess barrier function. In this work we describe and characterize a novel 96-well human gut organoid-derived monolayer system that enables medium/high-throughput quantitative assessment of candidate therapeutics. Normal human intestine differentiation patterns and barrier function were characterized and confirmed to recapitulate key aspects of in vivo biology. Next, cellular response to TNF- (a central driver of IBD) was determined using a diverse cadre of readouts.These outputs included transcription factor phosphorylation, target gene expression, cytokine/chemokine production, and barrier function. Additionally, we showed that TNF- pathway antagonists rescued damage caused by TNF- in a dose-dependent manner, indicating that this system is suitable for quantitative assessment of barrier modulating factors. Taken together, we have established a robust primary cell-based 96-well system capable of interrogating questions around mucosal response. This system is well suited to provide pivotal functional data to support translational target and drug discovery efforts.

immunology↗

bioRxiv2021

Assessing donor-to-donor variability in human intestinal organoid cultures

Donor-to-donor variability in primary human organoid cultures has not been well characterized. As these cultures contain multiple cell types, there is greater concern that variability could lead to increased noise. In this work we investigated donor-to-donor variability in human gut adult stem cell (ASC) organoids. We examined intestinal developmental pathways during culture differentiation in ileum- and colon-derived cultures established from multiple donors, showing that differentiation patterns were consistent among cultures. This finding indicates that donor-to-donor variability in this system remains at a manageable level. Intestinal metabolic activity was evaluated by targeted analysis of central carbon metabolites and by analyzing hormone production patterns. Both experiments demonstrated similar metabolic functions among donors. Importantly, this activity reflected intestinal biology, indicating that these ASC organoid cultures are appropriate for studying metabolic processes. This work establishes a framework for generating high confidence data using human primary cultures through thorough characterization of variability.

developmental biology↗