Selected Grantee Publications
- Clear All
- 14 results found
- Cardiovascular
- Stem Cells/Regenerative Medicine
- 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.
Differentiation Success of Reprogrammed Cells Is Heterogeneous In Vivo and Modulated by Somatic Cell Identity Memory
Zikmund et al., Stem Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/40086446
Nuclear reprogramming can change cellular fates, yet reprogramming efficiency is low, and the resulting cell types are often not functional. Researchers used nuclear transfer to Xenopus eggs to follow single cells during reprogramming in vivo. Results showed that the differentiation success of reprogrammed cells varies across cell types and depends on the expression of genes specific to the previous cellular identity. Subsets of reprogramming-resistant cells fail to form functional cell types and undergo cell death or disrupt normal body patterning. Reducing expression levels of genes specific to the cell type of origin leads to better reprogramming and improved differentiation trajectories. This study demonstrates that failing to reprogram in vivo is cell type specific and emphasizes the necessity of minimizing aberrant transcripts of the previous somatic identity for improving reprogramming. Supported by ORIP (R24OD031956).
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.
Local Tissue Response to a C-X-C Motif Chemokine Ligand 12 Therapy for Fecal Incontinence in a Rabbit Model
Ruetten et al., American Journal of Physiology—Gastrointestinal and Liver Physiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39745592
Obstetric anal sphincter injury (OASI) occurs in 2–7% of vaginal childbirths. Surgical interventions for OASI are suboptimal, with 30% of women reporting continued reduction in quality of life due to long-term fecal incontinence. Researchers used a 4- to 5-month-old female New Zealand white rabbit model for OASI to determine whether local C-X-C motif chemokine ligand 12 (CXCL12) injection reduces postinjury pathologies. Treatment with CXCL12 significantly reduced fibrosis. Untreated rabbits demonstrated reduced distinction of anal sphincter skeletal muscle layering and significantly increased the amount of fibrosis. Treatment with CXCL12 did not affect recruitment of CD34+ cells, the number of PAX7+ satellite cells, or innervation and vascularization of skeletal muscle. This pilot study demonstrates the potential of a novel therapeutic for OASI. Supported by ORIP (T32OD010957).
A Murine Model of Trypanosoma brucei-Induced Myocarditis and Cardiac Dysfunction
Crilly et al., Microbiology Spectrum. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11792545
Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases, HAT and AAT, respectively. Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models for T. brucei infection. A clinically relevant, reproducible murine model for T. brucei–associated cardiomyopathy is currently unavailable. The researchers developed a 7- to 10-week-old C57Bl/6J male and female mouse model for T. brucei infection that demonstrates myocarditis, elevated serum levels of NT-proBNP, and electrocardiographic abnormalities, recapitulating the clinical features of infection. The results demonstrate the importance of interstitial space in T. brucei colonization and provide a relevant, reproducible murine model to investigate the pathogenesis and potential therapeutics of T. brucei-mediated heart damage. Supported by ORIP (T32OD011089, S10OD026859), NCI, and NIA.
Preclinical Use of a Clinically-Relevant scAAV9/SUMF1 Vector for the Treatment of Multiple Sulfatase Deficiency
Presa et al., Communications Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/39870870
This study evaluates a gene therapy strategy using an adeno-associated virus (AAV)/SUMF1 vector to treat multiple sulfatase deficiency (MSD), a rare and fatal lysosomal storage disorder caused by mutations in the SUMF1 gene. Researchers delivered the functional gene to male and female Sumf1 knockout mice either neonatally or after symptom onset. Neonatal treatment via cerebral spinal fluid extended survival up to 1 year, alleviated MSD symptoms, and restored normal behavior and cardiac and visual function without toxicity. Treated tissues showed widespread SUMF1 expression and enzymatic activity. These findings support the translational potential of this gene replacement therapy for clinical use in MSD patients. Supported by ORIP (U42OD010921, U54OD020351, U54OD030187) and NCI.
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.
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.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
The Splicing Factor hnRNPL Demonstrates Conserved Myocardial Regulation Across Species and Is Altered in Heart Failure
Draper et al., FEBS Letters. 2024.
https://pubmed.ncbi.nlm.nih.gov/39300280/
The 5-year mortality rate of heart failure (HF) is approximately 50%. Gene splicing, induced by splice factors, is a post-transcriptional modification of mRNA that may regulate pathological remodeling in HF. Researchers investigated the role of the splice factor heterogenous nuclear ribonucleoprotein-L (hnRNPL) in cardiomyopathy. hnRNPL protein expression is significantly increased in a male C57BL/6 transaortic constriction–induced HF mouse model and in clinical samples derived from canine or human HF patients. Cardiac-restricted knockdown of the hnRNPL homolog in Drosophila revealed systolic dysfunction and reduced life span. This study demonstrates a conserved cross-species role of hnRNPL in regulating heart function. Supported by ORIP (K01OD028205) and NHLBI.