Biology subjects

Flaxman, C. S.

Publications and source records attributed to Flaxman, C. S..

3 recordsLinked to original sources

bioRxiv2025

Small things matter: Lack of extra-islet beta cells in Type 1 diabetes

Recent 3D analyses reported abundant, small beta-cell-rich endocrine objects (EOs) in the human pancreas. Here, we assessed morphological parameters of >262,000 EOs in pancreas sections from 220 donors with or without type 1 diabetes (T1D), ranging in age and disease duration. We observe many insulin (Ins)+/glucagon (Gluc)-EOs in donors without diabetes. Their relative contribution to the total endocrine area is greatest in early life (0-2y) but reduces thereafter. Strikingly, we show the virtual absence of Ins+Gluc- EOs in individuals with T1D, where only the medium and large EOs retain beta cells. We also report a lower EO density in T1D, especially in individuals diagnosed in early life. These findings suggest that extra-islet beta cells are impacted in the development of T1D, and their early loss is a characteristic feature. This new understanding has important implications for defining beta-cell mass, which may inform future screening and treatment strategies in T1D. HighlightsO_LIThe present extensive 2D studies confirm and extend recent 3D analyses of human pancreata, demonstrating that 50% of endocrine objects (EOs) are much smaller than classical islets of Langerhans and consist predominantly of beta cells (Ins+). C_LIO_LISmall insulin+ EOs comprise the largest proportion of the total endocrine area in early childhood and persist throughout the life course in donors without diabetes. C_LIO_LIThere is a shift towards larger EO size with increasing age, with the most pronounced changes in size occurring in the first few years of life. C_LIO_LISmall Ins+ EOs are virtually absent in individuals with type 1 diabetes, while the persisting EOs with beta cells are larger, suggesting a selective destruction of beta cells in small EOs. C_LIO_LIDevelopment of type 1 diabetes, particularly at an early age, is associated with fewer larger EOs in adulthood. This implies that the lack or early destruction of small Ins+ EOs may be detrimental to the generation of larger EOs. C_LI

pathology↗

bioRxiv2025

Morpho-functional timeline of progressive cystic fibrosis pancreatic exocrine and endocrine pathology derived from semi-quantitative scoring and AI-driven quantitativeimage analysis

Cystic fibrosis (CF) is associated with pancreatic exocrine insufficiency (PEI) early in life and diabetes in up to 50% of adults. The underlying CF-related sequential changes within the pancreas associated with exocrine and endocrine insufficiency remain incompletely understood due to scarcity of available human tissue, protracted disease course and absence of established robust and reproducible analytical approaches. This study aimed to develop and apply a systematic analysis cross-sectionally to CF pancreatic tissue samples from donors over a wide age range to construct a timeline related to the main exocrine and endocrine changes underlying progressive disease. Based on a histopathological semi-quantitative scoring system and AI-driven quantitative image analysis pancreatic changes were individually evaluated and classified according to three patterns: fibrotic; fibrotic and lipotic; and lipoatrophic. This systematic evaluation was applied to 29 CF and 58 control donors without pancreatic disease. Rapid loss of acinar tissue with virtually complete absence by the age of 7 years was confirmed, mirrored by fatty tissue replacement - changes underlying PEI and likely preceding progression towards diabetes. Ductal blockage by thickened secretions was associated with increasing ductal dilatation accompanied by peri-ductal fibrosis, followed by ductal loss with involution of associated fibrosis in parallel with increasing adipocyte proportional area (PA). Remaining ducts were relatively small surrounded by residual fibrosis. Islets became increasingly clustered initially surrounded by activated pancreatic stellate cells (PSCs) and fibrosis and then disorganised by interposing fibrotic tissue between endocrine cell regions and surrounded by residual collagen stranding in a lipoatrophic pancreas. Overall islet mass was not significantly reduced but {beta}-cell PA was significantly reduced from birth without further loss over time. We concluded that the natural history of pancreatic CF progresses inexorably from peri-ductal fibrosis to global fat replacement with relatively well-maintained islet mass but PSC-associated fibrotic islet remodelling circumstantially implicated in {beta}-cell failure.

pathology↗

bioRxiv2023

Developmentally dynamic changes in DNA methylation in the human pancreas

Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with >21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome, and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. To our knowledge, this represents the most extensive exploration of DNA methylation patterns during human fetal pancreas development, confirming the prenatal period as a time of major epigenomic plasticity.

genomics↗