Selected Grantee Publications
- Clear All
- 21 results found
- nhlbi
- niddk
- Microscopy
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.
Early Results of an Infant Model of Orthotopic Cardiac Xenotransplantation
Mitchell et al., Journal of Heart and Lung Transplantation. 2025.
https://pubmed.ncbi.nlm.nih.gov/39778609
This study evaluated the potential of genetically engineered pig hearts for human pediatric heart failure patients, with 11 infantile pig heart transplants performed in size-matched infant baboons (Papio anubis) (sex not specified). All grafts supported normal cardiac functions post-operatively, and six animals survived beyond 3 months. While early cardiac function was not a limiting factor for survival, systemic inflammation led to pulmonary edema and pleural effusions, which impeded long-term outcomes. These findings highlight the feasibility of cardiac xenotransplantation in infants and underscore the need for targeted therapies to manage inflammation and improve survival. Supported by ORIP (P40OD024628) and NHLBI.
Prostatic Escherichia coli Infection Drives CCR2-Dependent Recruitment of Fibrocytes and Collagen Production
Scharpf et al., Disease Models & Mechanisms. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11789281
In men, lower urinary tract dysfunction (LUTD) is commonly linked to prostatic collagen accumulation through inflammation-mediated mechanisms. Researchers used 8- to 10-week-old male reporter mice, exposed to either sterile phosphate buffered saline (PBS) or Escherichia coli, to identify that circulating Lyz2+S100a4+Gli1+ myeloid-derived cells are recruited to the prostate to drive inflammation and collagen synthesis. Researchers also used 8- to 10-week-old male Ccr2‑/ - null and Ccr2+/- control mice, exposed to either sterile PBS or E. coli, to determine if Ccr2 is necessary for the fibrotic response to prostatic uropathogen infection. Results demonstrated that CCR2+ cells mediate the collagen abundance and fibrotic response to prostate inflammation. This study elucidates the cell types underlying prostate fibrosis and can be utilized to develop targeted therapies. Supported by ORIP (T32OD010957), NCI, NIDDK, and NIEHS.
A Comprehensive Atlas of AAV Tropism in the Mouse
Walkey et al., Molecular Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39863928
Over the past three decades, adeno-associated viruses (AAVs) have emerged as the leading viral vector for in vivo gene therapy. This study presents a comprehensive atlas of AAV tropism in male and female mice, evaluating 10 naturally occurring AAV serotypes across 22 tissues using systemic delivery. Researchers employed a fluorescent protein activation approach to visualize AAV transduction patterns and detected transduction of unexpected tissues, including in adrenal glands, testes, and ovaries. Biodistribution closely matched the fluorescent signal intensity. This publicly available data set provides valuable insights into AAV vector targeting and supports optimal serotype selection for basic research and preclinical gene therapy applications in murine models. Supported by ORIP (U42OD026645, U42OD035581, U42OD026635), NCI, NHLBI, NICHD, and NIDDK.
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.
Single-Cell Transcriptomics Predict Novel Potential Regulators of Acute Epithelial Restitution in the Ischemia-Injured Intestine
Rose et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39853303
Following ischemia in the small intestine, early barrier restoration relies on epithelial restitution to reseal the physical barrier and prevent sepsis. Pigs share a similar gastrointestinal anatomy, physiology, and microbiota with humans. Researchers used neonatal and juvenile, 2- to 6-week-old male and female Yorkshire cross pigs to determine upstream regulators of restitution. Single-cell sequencing of ischemia-injured epithelial cells demonstrated two sub-phenotypes of absorptive enterocytes, with one subset presenting a restitution phenotype. Colony-stimulating factor-1 (CSF1) was the only predicted upstream regulator expressed in juvenile jejunum compared with neonatal jejunum. An in vitro scratch wound assay using IPEC-J2 cells showed that BLZ945, a colony-stimulating factor 1 receptor antagonist, inhibited restitution. Ex vivo ischemia-injured neonatal pig jejunum treated with exogenous CSF1 displayed increased barrier function. This study could inform future research focused on developing novel therapeutics for intestinal barrier injury in patients. Supported by ORIP (T32OD011130, K01OD028207), NCATS, NICHD, and NIDDK.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
The Widely Used Ucp1-Cre Transgene Elicits Complex Developmental and Metabolic Phenotypes
Halurkar et al., Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/39824816
Bacterial artificial chromosome technology is instrumental to mouse transgenics, including in studies of highly thermogenic brown adipose tissue and energy-storing white adipose tissue. Researchers discovered that male and female Ucp1-CreEvdr transgenic mice, which are commonly used to study fat tissue, may have unintended effects on metabolism and development. Findings revealed that these mice show changes in both brown and white fat function and disruptions in gene activity, suggesting broader physiological impacts than previously thought. This study emphasizes the need for careful validation of genetic tools in research to ensure accurate results, highlighting the potential concerns in using the Ucp1-CreEvdr model in metabolic and developmental studies. Supported by ORIP (R21OD034470, R21OD031907) NCATS, NIDCR, and NIDDK.
The Buoyancy of Cryptococcal Cells and Its Implications for Transport and Persistence of Cryptococcus in Aqueous Environments
Jimenez et al., mSphere. 2024.
https://pubmed.ncbi.nlm.nih.gov/39601568/
Cryptococcosis is a major fungal pathogen that causes life-threatening infections. Researchers discovered that Cryptococcus has unique buoyancy properties that help with its survival and spread through water transport. This study explores how these fungal cells remain suspended in liquid, potentially enhancing their ability to survive in their surroundings and infect new hosts. Understanding the role of cellular buoyancy in Cryptococcus transport could improve strategies to prevent spread in aqueous settings, offering new insights into fungal infection risks. Supported by ORIP (T32OD011089), NIAID, and NHLBI.
Lipid Nanoparticle-Mediated mRNA Delivery to CD34+ Cells in Rhesus Monkeys
Kim et al., Nature Biotechnology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578569
Blood cells, which are derived from hematopoietic stem cells (HSCs), promote pathologies including anemia, sickle cell disease, immunodeficiency, and metabolic disorders when dysfunctional. Because of the morbidity that results from the bone marrow mobilization and chemotherapy patient conditioning of current HSC therapies, novel treatment strategies that deliver RNA to HSCs are needed. Researchers found a lipid nanoparticle (LNP), LNP67, that delivers messenger RNA (mRNA) to murine HSCs in vivo and human HSCs ex vivo without the use of a cKit-targeting ligand. When tested in 7- to 8-month-old male and female rhesus monkeys, LNP67 successfully delivered mRNA to CD34+ cells and liver cells without adverse effects. These results show the potential translational relevance of an in vivo LNP–mRNA drug. Supported by ORIP (U42OD027094, P51OD011107), NIDDK, and NCATS.