bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.10.14.682181

Modeling physiological insulin sensitivity and pre-diabetic insulin resistance in multiple hPSC-derived cell types

Friesen, M.·Jaenisch, R.
View original source ↗Export metadata ↓

Abstract

Recently, we demonstrated the development of a human pluripotent stem cell (hPSC)-derived adipocyte (fat cell) model with physiological insulin signaling. For the first time, a human in vitro adipocyte cell model has an insulin response similar to in vivo human adipocytes. We next leveraged this protocol to study the early stages of insulin resistance preceding Type 2 Diabetes, by exposing these cells to diabetic patient levels of hyperinsulinemia. This resulted in mild insulin resistance on all of the aforementioned phenotypes, reminiscent of early T2D development in humans. This is a powerful model to study the mechanisms of T2D development and the underlying molecular pathology. However, while adipocytes are an important metabolic cell type, insulin resistance and T2D are a whole-body affliction, involving many other cell types. To broaden the impact of our work and increase the excitement of the field for the study of insulin signaling and resistance, we expanded our protocol to a panel of 8 other hPSC-derived cell types. We demonstrate physiologically relevant insulin response for each cell type, and we highlight that our insulin-resistance inducing conditions blunt the insulin response in every cell type. Additionally, we validate that key cell identity markers are not lost during this adaptation. By adapting a simple, defined protocol to a wide panel of human in vitro cell types, we can now investigate the cell-autonomous origins of insulin resistance under physiologically relevant conditions.

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Friesen, M., Jaenisch, R.. 2025-10-16. Modeling physiological insulin sensitivity and pre-diabetic insulin resistance in multiple hPSC-derived cell types. https://doi.org/10.1101/2025.10.14.682181

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity

The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.

cell biology↗
bioRxiv2026

Nucleosome Core Allostery Governs Chromatin Recognition and Cell Fate

Nucleosomes regulate chromatin folding, accessibility, and factor recruitment. Current models primarily attribute these functions to histone tail modifications, while the core is largely viewed as a structural scaffold. Yet subtle changes within the nucleosome core can produce profound functional consequences, and the mechanisms underlying these effects remain unclear. Here, we describe nucleosome core allostery as a fundamental principle of chromatin regulation that amplifies the impact of minimal nucleosome variations. Leveraging natural differences between H2A.Z variants, we show that the nucleosome core encodes distinct conformational dynamics that propagate allosterically, thereby controlling nucleosome accessibility and recognition by chromatin factors. As a result, a single buried amino acid substitution alone is sufficient to reprogram nucleosome dynamics and bias cell identity. Our findings establish the nucleosome core as an allosteric regulatory module and provide a generalizable framework for how subtle variation within nucleosomes is amplified into diverse biological outcomes in development and disease.

cell biology↗
bioRxiv2026

YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells must proliferate to expand the cell population, yet terminal differentiation requires this proliferative state to end. How signaling controls the duration of this proliferative window remains poorly understood. Using adipogenesis and live single-cell imaging of differentiation, cell-cycle, and ERK-activity reporters, we show that YAP and TAZ coordinate progenitor expansion with differentiation commitment by regulating ERK dynamics. YAP/TAZ maintain cells in a fluctuating high-ERK state that promotes proliferation while actively keeping the differentiation driver PPARG below the threshold for irreversible commitment. Crucially, this differentiation block is not explained by proliferation alone: inhibiting CDK4/6 or AKT suppressed proliferation without restoring differentiation, whereas MEK-ERK inhibition restored differentiation even when YAP/TAZ activity remained high. As YAP/TAZ activity decreases, dampened ERK fluctuations trigger PPARG activation. These findings support a self-limiting model in which YAP/TAZ-driven progenitor expansion progressively increases cell density and contact-dependent Hippo signaling, reducing YAP/TAZ activity and terminating the proliferative phase. Consequently, transient YAP/TAZ activation expands the progenitor pool while preserving subsequent differentiation, whereas sustained activation suppresses commitment. Together, these findings identify YAP/TAZ-controlled ERK dynamics as the nexus coordinating progenitor expansion with terminal differentiation and suggest that slower density-dependent Hippo feedback may set the duration of this proliferative window to regulate differentiated cell-number output.

cell biology↗