Biology subjects

Uslu, M.

Publications and source records attributed to Uslu, M..

4 recordsLinked to original sources

bioRxiv2026

Inter-organ communication shapes human metabolic tissue states and resolves anti-diabetic drug response modes in a six-tissue microphysiological system

Systemic glucose regulation depends on coordinated signaling among metabolically specialized tissues, yet most human in vitro models capture only limited portions of this network. Here, we developed and benchmarked a perfused human six-tissue MPS by combining AnthroHive, a recirculating perfusion platform, with MOTIVE-6, a six-compartment Multiorgan Tissue Interaction Vessel, to culture human gut epithelium, pancreatic islets, liver organoids, adipocytes, skeletal muscle, and midbrain-patterned brain organoids in a microphysiological system. Shared perfusion redirected engineered tissue states toward tissue-aligned metabolic, endocrine, absorptive, contractile, and neural-associated programs while reducing selected isolation-associated stress and remodeling signatures. Under High nutrient conditions, however, multi-tissue interaction shifted liver and islet responses toward inflammatory and nutrient-stress-associated gene expression, indicating context-dependent effects of cross-compartment signaling. Graded nutrient exposure resolved a staged circuit trajectory: Low nutrient conditions supported maintenance-associated programs, Mid nutrient exposure induced compensatory endocrine and anabolic remodeling with declining net glucose depletion, and High nutrient exposure shifted the system toward stress-associated metabolic dysfunction. Under High conditions, metformin and semaglutide produced distinct response modes. Metformin preserved circuit-level glucose handling without increasing insulin or C-peptide accumulation, while semaglutide remodeled gut, brain organoid, islet, and liver organoid transcriptional programs linked to nutrient sensing, epithelial maintenance, endocrine signaling, and neurometabolic state. Together, this study establishes a benchmarked human six-tissue MPS resource, paired with tissue-resolved transcriptomic, shared-media metabolomic, functional, endocrine, and inflammatory datasets, for investigating how tissue interaction, nutrient availability, and metabolic therapies reshape glucose-regulatory networks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/726943v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@181cdfforg.highwire.dtl.DTLVardef@fb211eorg.highwire.dtl.DTLVardef@13b7284org.highwire.dtl.DTLVardef@1db7543_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Trapecar, M. (2026) https://BioRender.com/a4tl7nv

bioengineering↗

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↗

bioRxiv2025

Single-Cell Analysis Reveals Tissue-Specific T Cell Adaptation and Clonal Distribution Across the Human Gut-Liver-Blood Axis

Understanding T cell clonal relationships and tissue-specific adaptations is crucial for deciphering human immune responses, particularly within the gut-liver axis. We performed paired single-cell RNA and T cell receptor sequencing on matched colon (epithelium, lamina propria), liver, and blood T cells from the same human donors. This approach tracked clones across sites and assessed microenvironmental impacts on T cell phenotype. While some clones were shared between blood and tissues, colonic intraepithelial lymphocytes (IELs) exhibited limited overlap with lamina propria T cells, suggesting a largely resident population. Furthermore, tissue-resident memory T cells (TRM) in the colon and liver displayed distinct transcriptional profiles. Notably, our analysis suggested that factors enriched in the liver microenvironment may influence the phenotype of colon lamina propria TRM. This integrated single-cell analysis maps T cell clonal distribution and adaptation across the gut-liver-blood axis, highlighting a potential liver role in shaping colonic immunity.

immunology↗

bioRxiv2020

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34low cells) and human (CD34+, CD133+, and ALDHhi cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including Hif-1, Hif-2 and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies.

molecular biology↗