Selected Grantee Publications
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- 18 results found
- nci
- Microbiome
- Stem Cells/Regenerative Medicine
Small-Diameter Artery Grafts Engineered from Pluripotent Stem Cells Maintain 100% Patency in an Allogeneic Rhesus Macaque Model
Zhang et al., Cell Reports Medicine. 2025.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00075-8
Globally, the leading cause of death is occlusive arterial disease, but surgical revascularization improves patient prognosis and reduces mortality. Vascular grafts often are needed in coronary bypass surgery for surgical revascularization. However, the clinically approved option for small-diameter revascularization is autologous vascular grafts, which require invasive harvesting methods, and many patients lack suitable vessels. Researchers developed a novel method for graft development using arterial endothelial cells (AECs), derived from pluripotent stem cells (PSCs), on expanded polytetrafluoroethylene using specific adhesion molecules. This study used a 6- to 13-year-old male rhesus macaque arterial interposition grafting model. The major histocompatibility complex mismatched wild-type (MHC-WT) AEC grafts were successful when implanted in rhesus macaques and attracted host cells to the engraftment, leading to 100% patency for 6 months. The results highlight a novel strategy for generating artery grafts from PSC-derived MHC-WT AECs that overcomes current challenges in graft development and may have future clinical applications. Supported by ORIP (P51OD011106, S10OD023526), NCI, and NHLBI.
In Vivo Expansion of Gene-Targeted Hepatocytes Through Transient Inhibition of an Essential Gene
De Giorgi et al., Science Translational Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937884
This study explores Repair Drive, a platform technology that selectively expands homology-directed repair for treating liver diseases in male and female mice. Through transient conditioning of the liver by knocking down an essential gene—fumarylacetoacetate hydrolase—and delivering an untraceable version of that essential gene with a therapeutic transgene, Repair Drive significantly increases the percentage of gene-targeted hepatocytes (liver cells) up to 25% without inducing toxicity or tumorigenesis after a 1-year follow-up. This also resulted in a fivefold increase in expression of human factor IX, a therapeutic transgene. Repair Drive offers a promising platform for precise, safe, and durable correction of liver-related genetic disorders and may expand the applicability of somatic cell genome editing in a broad range of liver diseases in humans. Supported by ORIP (U42OD035581, U42OD026645), NCI, NHLBI, and NIDDK.
Integrative Multi-omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes in Ovarian Cancer
Rosario et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39638782
Recurrent ovarian cancer (OC) is the deadliest gynecological malignancy, with a 5-year survival rate of 50% and a median progression-free survival (PFS) of 1.9 to 2.1 months. A trial cohort of 40 patients was treated with a combination of the anti-PD-1 pembrolizumab, the anti–vascular endothelial growth factor bevacizumab, and cyclophosphamide. The investigators conducted a multi-omics analysis—including transcriptomic analysis, digital spatial profiling, 16s-rRNA sequencing, and metabolomics—to understand the underlying mechanisms for the enhanced PFS to a median of 10.2 months and overall response rate of 47.5%. Multi-omics analysis highlighted the formation of tertiary lymphoid structures known to improve responses to immunotherapy, differential microbial patterns, and alterations in the metabolites in three key metabolism pathways that enhanced immune response in patients to produce a durable clinical response. These findings highlight the importance of the tumor microenvironment and the gut microbiome, along with its metabolites, in elevating the efficacy of the cocktail therapy in recurrent OC patients, thereby enhancing their survival and quality of life. Supported by ORIP (S10OD024973) and NCI.
Bone Marrow Transplantation Increases Sulfatase Activity in Somatic Tissues in a Multiple Sulfatase Deficiency Mouse Model
Presa et al., Communications Medicine. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11502872/pdf/43856_2024_Article_648.pdf
Multiple Sulfatase Deficiency (MSD) is a rare genetic disorder where patients demonstrate loss of function mutations in the SUMF1 gene, resulting in a severe reduction in sulfatase activity. This enzyme deficiency causes impaired lysosomal function and widespread inflammation, leading to clinical manifestations like neurodegeneration, vision and hearing loss, and cardiac disease. The researchers evaluated the therapeutic potential of hematopoietic stem cell transplant (HSCT) to initiate cross-correction, where functional sulfatase enzymes secreted from the healthy donor cells are taken up to restore function in enzyme-deficient host cells. Bone marrow from healthy male and female B6-Sumf1(+/+) mice were transplanted into B6-Sumf1(S153P/S153P) mice, a model for MSD. The results showed that HSCT is suitable to rescue sulfatase activity in peripheral organs, such as the liver, spleen, and heart, but is not beneficial alone in inhibiting the central nervous system pathology of MSD. Supported by ORIP (U54OD020351, U54OD030187, U42OD010921) and NCI.
Time of Sample Collection Is Critical for the Replicability of Microbiome Analyses
Allaband et al., Nature Metabolism. 2024.
https://pubmed.ncbi.nlm.nih.gov/38951660/
Lack of replicability remains a challenge in microbiome studies. As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design will be critical. Researchers conducted a retrospective analysis of 16S amplicon sequencing studies in male mice. They report that sample collection time affects the conclusions drawn from microbiome studies. The lack of consistency in the time of sample collection could help explain poor cross-study replicability in microbiome research. The effect of diurnal rhythms on the outcomes and study designs of other fields is unknown but is likely significant. Supported by ORIP (T32OD017863), NCATS, NCI, NHLBI, NIAAA, NIAID, NIBIB, NIDDK, and NIGMS.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity
Nam, Cancer Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38588407/
Tumor-initiating cells can survive in harsh environments via stress tolerance and metabolic flexibility; studies on this topic can yield new targets for cancer therapy. Using cultured cells and live human surgical biopsies of non-small cell lung cancer, researchers demonstrated that nutrient stress drives a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. This cascade results from upregulation of integrin αvβ3, a cancer stem cell marker. In mice, pharmacological or genetic targeting prevented lung cancer cells from evading the effects of nutrient stress, thus blocking tumor initiation. This work suggests that this molecular pathway leads to cancer stem cell reprogramming and could be linked to metabolic flexibility and tumor initiation. Supported by ORIP (K01OD030513), NCI, NIGMS, and NINDS.
Intestinal Epithelial Adaptations to Vertical Sleeve Gastrectomy Defined at Single-Cell Resolution
Koch-Laskowski et al., Genomics. 2024.
https://pubmed.ncbi.nlm.nih.gov/38309446/
Perturbations in the intestinal epithelium have been linked to the pathogenesis of metabolic disease. Bariatric procedures, such as vertical sleeve gastrectomy (VSG), cause gut adaptations that induce robust metabolic improvements. Using a male mouse model, the authors assessed the effects of VSG on different cell lineages of the small intestinal epithelium. They show that Paneth cells display increased expression of the gut peptide Reg3g after VSG. Additionally, VSG restores pathways pertaining to mitochondrial respiration and cellular metabolism, especially within crypt-based cells. Overall, this work demonstrates how adaptations among specific cell types can affect gut epithelial homeostasis; these findings can help researchers develop targeted, less invasive treatment strategies for metabolic disease. Supported by ORIP (F30OD031914), NCI, and NIDDK.
Antibiotic-Induced Gut Dysbiosis Elicits Gut–Brain–Axis Relevant Multi-Omic Signatures and Behavioral and Neuroendocrine Changes in a Nonhuman Primate Model
Hayer et al., Gut Microbes. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826635/
Gut microbiome–mammalian cell interactions influence the development of metabolic, immune-mediated, and neuropsychiatric disorders. Dysbiosis of the gut microbiome has been linked to behavioral characteristics in previous nonhuman primate (NHP) studies, but additional studies using NHPs are necessary to understand microbiota–gut–brain communication. The authors sought to evaluate whether antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut–brain axis disruption in common marmosets of both sexes. For the first time in an NHP model, this study demonstrated that antibiotics induce gut dysbiosis, alter gut metabolites relevant to gut–brain communication, affect neuroendocrine responses in response to stressful stimuli, and change social behavior. Supported by ORIP (K01OD030514), NCI, and NIGMS.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
Assessment of Various Standard Fish Diets on Gut Microbiome of Platyfish Xiphophorus maculatus
Soria et al., Journal of Experimental Zoology Part B. 2023.
https://onlinelibrary.wiley.com/doi/10.1002/jez.b.23218
Diet is an important factor affecting experimental reproducibility and data integration across studies. Reference diets for nontraditional animal models are needed to control diet-induced variation. In a study of the dietary impacts on the gut microbiome, researchers found that switching from a custom diet to a zebrafish diet altered the Xiphophorus gut microbiome. Their findings suggest that diets developed specifically for zebrafish can affect gut microbiome composition and might not be optimal for Xiphophorus. Supported by ORIP (R24OD011120, R24OD031467, P40OD011021) and NCI.