Coate, K. | Search bioRxiv

bioRxiv2026

MAFB is essential for the maintenance of adult human α-cell identity and glucagon secretion

Dysregulated hormone secretion and erosion of endocrine cell identity are features of type 1 and type 2 diabetes, but the transcriptional programs maintaining adult human islet identity and function remain poorly defined. The large MAF transcription factor MAFB is expressed in human - and {beta}-cells, marks their most functionally mature subpopulations, and is downregulated in diabetes, but its role in adult human islets has not been tested directly. Using shRNA-mediated MAFB knockdown (KD) in whole and CD26+ -cell-enriched human pseudoislets, we found that whole pseudoislet MAFB KD impaired glucagon synthesis and secretion while only modestly reducing insulin content and cAMP-potentiated insulin release. Single-cell profiling detected no {beta}-cell transcriptional response beyond MAFB KD itself, consistent with buffering by the related {beta}-cell-enriched MAFA transcription factor. In contrast, -cell-restricted MAFB KD unmasked a cell-autonomous requirement for MAFB in stimulus-secretion coupling. MAFB deficiency also destabilized -cell identity, downregulating canonical -cell and neuroendocrine secretory genes while ectopically inducing mesenchymal and extracellular matrix remodeling programs. In addition, MAFB-dependent downregulation of electron transport chain genes was confined to a large -cell subcluster, manifesting as impaired islet-wide mitochondrial respiration within the broader -cell population. Together, these findings identify MAFB as an essential adult human -cell maintenance factor that links diabetes-associated downregulation to impaired glucagon secretion, -cell identity erosion, and mitochondrial dysfunction. RESEARCH IN CONTEXTO_LIWhat is already known about this subject? O_LIMAFB is expressed in adult human - and {beta}-cells, marks their most functionally mature subpopulations, and is downregulated in type 1 and type 2 diabetes C_LIO_LIIn human stem cell models, MAFB is essential for generating insulin-producing {beta}-like cells, whereas glucagon-producing -like cells are reduced but still formed C_LIO_LINeither model addresses adult human islets: rodent MafB becomes -cell restricted after birth, and stem cell models capture differentiation, not maintenance C_LI C_LIO_LIWhat is the key question? O_LIIs MAFB required to maintain identity and secretory function in adult human islet cells? C_LI C_LIO_LIWhat are the new findings? O_LIMAFB knockdown in primary human pseudoislets impaired glucagon synthesis and secretion but minimally affected {beta}-cells, consistent with buffering by MAFA C_LIO_LIKnockdown in CD26+ -cell-enriched pseudoislets revealed a cell-autonomous requirement for MAFB in stimulus-secretion coupling, and destabilized -cell identity by inducing mesenchymal and extracellular matrix programs C_LIO_LIMAFB loss downregulated electron transport chain genes in the largest -cell subcluster and reduced mitochondrial respiration C_LI C_LIO_LIHow might this impact on clinical practice in the foreseeable future? O_LIPreserving MAFB activity in adult human -cells may represent a strategy to limit -cell dysfunction in diabetes C_LI C_LI

physiology↗

bioRxiv2026

QuantEM: An optimized platform of vision transformer-based models for segmentation and analysis of electron microscopy data

Electron microscopy (EM) is essential for resolving cellular ultrastructure, yet quantitative analysis remains limited by labor-intensive segmentation and the scarcity of generalizable models. Here we present QuantEM, an open-source platform for segmentation and analysis of EM data across imaging modalities, tissues, and species. We assembled the largest curated collection of intracellular EM datasets to date, comprising over 15,000 two-dimensional images and 1,700 three-dimensional acquisitions from more than 600 datasets, including nearly 4,000 newly released acquisitions. Using this resource, we trained an EM-specific vision transformer foundation model and systematically optimized adaptation strategies for organelle segmentation. QuantEM provides pretrained models for mitochondria, endoplasmic reticulum, nuclei, and lipid droplets, integrated with interactive proofreading and downstream quantitative analyses through standalone and napari interfaces. Across diverse naive datasets, QuantEM consistently matches or exceeds existing models on zero-shot segmentation while requiring less data for finetuning. We further demonstrate its utility by revealing previously unrecognized subcellular compartmentation of hepatic glucokinase using immuno-electron microscopy.

cell biology↗