Biology subjects

Dorrell, C.

Publications and source records attributed to Dorrell, C..

3 recordsLinked to original sources

bioRxiv2025

In vivo assessment of differential toxicity of cancer treatment drugs in Fanconi Anemia

Fanconis Anemia (FA) is a DNA repair disorder with a very elevated risk of cancer, especially squamous cell carcinomas (SCC). Many cancer chemotherapy agents induce DNA damage, are highly toxic in FA, and cannot be safely used in this population. The potential differential toxicity to FA patients of many new drugs being explored for use in SCC is unknown. To evaluate such compounds of unknown toxicity for use in FA cancers, we developed a sensitive in vivo bone marrow repopulation competition assay in mice. We found that afatinib, alisertib and everolimus exhibited no significant differential toxicity in this system. Therefore, these drugs are candidates for chemotherapy of cancers in human FA patients. Our competitive repopulation assay provides a robust method to screen novel chemotherapy agents for their safety in FA. Summary- We developed a mouse model system for evaluating differential toxicity of cancer chemotherapy drugs on Fanconi Anemia mutant hematopoietic cells in vivo. - Different drugs resulted in either increases, decreases, or neutral wildtype to Fanconi mutant cell ratios permitting robust assessment of their safety in FA.

cancer biology↗

bioRxiv2025

Glucagon and GLP-1 Accelerate Pseudo-Islet Assembly and Unmask Sex-Specific Islet Fragmentation Dynamics

Pancreatic hormones are best known for their role in regulating blood sugar levels as well as islet cell function and proliferation. However, their impact on maintaining and inducing cell aggregation in culture remains under-explored. In this study, we investigated the effects of glucagon (GCG) and glucagon-like-peptide 1(GLP-1) on the formation and integrity of human islet clusters. Native human islets were dissociated and sorted into pure -, {beta}-, and {delta}-cell populations using antibody-based fluorescence-activated cell sorting (FACS). The sorted cells were then co-cultured with mouse endothelial MS1 cells in suspension to generate pseudo-islets of varying cell composition. Hormonal supplementation with GCG or GLP-1 versus blank was administered during the tissue culture phase. Hormone-treated pseudo-islets formed faster, dependent on the cellular composition and the sex of the donor. In parallel, we also exposed native islets, maintained in suspension without prior dissociation or sorting, to hormone supplementation. These islets exhibited accelerated fragmentation under hormone treatment compared to controls, again dependent on donor sex with islets from female donors fragmenting faster than from male donors. These findings suggest that GCG and GLP-1 enhance pseudo-islet formation and affect the structural integrity of native islets in a sex-specific manner, offering insights into islet biology and implications for diabetes research and therapy. Article HighlightsWe established a manipulatable, expandable human pseudo-islet platform to investigate islet morphogenesis, architecture, and intercellular signaling. We examined the contribution of individual -, {beta}-, and {delta}-cell populations and assessed how glucagon (GCG) and glucagon-like peptide-1 (GLP-1) modulate islet integrity in culture. In native islets, hormonal supplementation attenuated fragmentation in male donors but accelerated it in females. In pseudo-islets, cellular composition was the predominant determinant of maturation versus fragmentation, with donor sex exerting a secondary influence. We present methodological guidelines for generating and maintaining human pseudo-islets, thereby providing a framework to optimize donor selection, culture conditions, and experimental design in diabetes research.

biochemistry↗

bioRxiv2021

Generation of functional ciliates cholangiocytes from human pluripotent stem cells

The derivation of mature functional cholangiocytes from human pluripotent stem cells (hPSCs) would provide a model for studying the pathogenesis of cholangiopathies and for developing novel therapies to treat them. Current differentiation protocols are not efficient and give rise to cholangiocytes that are not fully mature, limiting their therapeutic applications. Here, we describe a new strategy to generate functional hPSC-derived cholangiocytes that display many characteristics of mature bile duct cells including high levels of CFTR and the presence of primary cilia capable of sensing flow. With this level of maturation, these cholangiocytes are amenable for testing the efficacy of new cystic fibrosis drugs and for studying the role of cilia in cholangiocyte development and function. Transplantation studies showed that the mature cholangiocytes generate ductal structures in the liver of immunocompromised mice providing the first indication that it may be possible to develop cell-based therapies to restore bile duct function in patients with biliary disease.

cell biology↗