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Biology subjects

McGilvray, I.

Publications and source records attributed to McGilvray, I..

4 recordsLinked to original sources

High-resolution spatial transcriptomics of adult and pediatric human liver with Visium HD

The liver is composed of diverse cell populations that coordinate essential metabolic and immune functions. Single-cell transcriptomics has advanced characterization of liver cellular composition, but dissociation of tissue to single-cells can introduce biases through the enrichment or depletion of cell types. Spatial transcriptomics is a complementary approach to avoid inherent bias for cell populations and to add important spatial context. The Visium HD spatial transcriptomics technology from 10X Genomics enables high-resolution spatial mapping of gene expression in tissue samples with a bin width of 2{micro}m enabling quantification of transcripts at a sub-cellular resolution. We applied Visium HD to three healthy human liver donor samples, from two adult and one pediatric donor. We identified cell types by clustering 8{micro}m bins and integration with single-cell reference maps. Differential expression analyses identified spatially distinct gene expression resulting in development of a high-resolution map of the liver. This resource provides cell-level and spatially-resolved insights into the cellular and anatomical heterogeneity of the liver to serve as a resource for researchers to identify disease-specific spatial signatures and novel therapeutic targets.

genomics↗

Consensus molecular subtypes define distinct evolutionary trajectories of biliary tract cancers

Introduction Biliary tract cancer (BTC) comprises a family of rare malignancies subclassified by anatomy and pathology. However, this scheme may obscure shared biology and limit patient stratification. Objectives We tested whether BTC heterogeneity can be explained by coherent latent axes and evaluated the potential to unify diverse clinical and genomic factors under a tractable biological framework Methods We performed whole-genome and transcriptome sequencing of 180 tumors enriched for tumor cells by laser capture microdissection to identify shared programs in BTC. Results Network integration across transcriptomic classes identified two consensus cancer subtypes (CCS). CCS segregated with anatomical location of primary tumor and gene expression marker analyses suggest subtypes reflect tumor cell of origin differences. CCS displayed strikingly divergent molecular landscapes, explaining more variance than anatomical location of primary tumor. CCS-B tumors were mutationally loaded with clock-like and APOBEC signatures and extrachromosomal DNA, whereas CCS-A tumors were characterized by chromosome-arm deletions. Conclusion Our approach showed that harnessing the genomic and transcriptomic diversity of BTC uncovers novel biology and improves stratification.

cancer biology↗

Scalable expansion and hepatic zone maturation of hepatic progenitor cells from human pluripotent stem cells

Scalable generation of functionally mature hepatocytes from human pluripotent stem cells (hPSCs) is vital for regenerative medicine, disease modeling, and drug screening. We present a modular differentiation platform that enables serial expansion and cryopreservation of hepatic progenitors (hepatoblasts; HBs), supporting efficient downstream maturation. By modulating bile acid signaling with FGF19 and culturing under hypoxia, we preserved HB proliferation and bipotency. Subsequent thyroid hormone treatment induced alpha-fetoprotein-negative, albumin-positive hepatocytes, while WNT pathway modulation promoted zonal identity, mimicking in vivo hepatic metabolic heterogeneity. Zonation was confirmed by differential drug-metabolizing enzyme activity, mitochondrial function, and enhanced engraftment in a liver injury mouse model. To evaluate translational relevance, mature hepatocytes were incorporated into extrusion-based 3D bioprinted constructs, which maintained hepatic viability and function. This integrated strategy of combining progenitor cell banking, zonation control, and tissue engineering offers a scalable and clinically relevant approach for generating functional human liver tissue suitable for therapeutic development.

cell biology↗

A Single-Cell Atlas Of Human Pediatric Liver Reveals Age-Related Hepatic Gene Signatures

Background & AimsThe liver plays a critical role in metabolism and immune function, yet the contributions of its heterogeneous cell types to these processes remain unclear. While most liver studies focus on adults, pediatric liver diseases often present differently, underscoring the need for age-specific research. Approach & ResultsTo better understand cellular drivers of childhood liver diseases, we generated single-cell RNA-seq (scRNA-seq) maps of the normal pediatric liver and used this map to examine disease-related populations in biopsies from pediatric patients with Intestinal Failure-Associated Liver Disease (IFALD). The normal pediatric liver map consists of 42,660 cells from 9 donors aged 2-17 years. Compared to normal adult liver (26,372 cells; 7 donors, age 26-69) pediatric livers exhibited differences in myeloid populations. Specifically, pediatric Kupffer-like cells (MARCO+C1QA+VSIG4+) exhibited higher expression of immune activation genes, including CCL4, CCL3 and IL1B. In vitro stimulation confirmed more IL1-{beta} secreting myeloid cells in pediatric versus adult livers, supporting these findings. Using the pediatric atlas as a reference, we analyzed three IFALD biopsies (11,969 cells; 3 donors, ages 4 months-9 years) and identified increased expression of fibrosis-associated genes (e.g., LY96) in Kupffer-like cells. Additionally, mesenchymal cells in IFALD showed fibrotic gene modules resembling adult liver cells more than healthy pediatric cells. These signatures, undetectable when comparing IFALD to adult liver alone, highlighting the value of a pediatric map. ConclusionsTaken together, our healthy pediatric liver atlas reveals distinct age-related signatures and provides background against which to interpret pediatric liver disease data. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/649149v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@8d4131org.highwire.dtl.DTLVardef@1b336d2org.highwire.dtl.DTLVardef@d43ddeorg.highwire.dtl.DTLVardef@29fadf_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗