Biology subjects

Houtekamer, R. M.

Publications and source records attributed to Houtekamer, R. M..

5 recordsLinked to original sources

bioRxiv2026

Mechanical strain of the intestinal epithelium directs absorptive lineage maturation

The intestinal epithelium is continuously subjected to a variety of mechanical forces, including extrinsic peristaltic contractions and intrinsic tensile forces generated by epithelial cell migration. Yet, how these mechanical cues influence the cellular processes underlying intestinal homeostasis remains poorly understood. In this study, we examine the impact of mechanical forces on intestinal cell dynamics by applying controlled external stretch to intestinal organoids, combined with high-throughput single-cell transcriptomic profiling. Our analyses reveal that prolonged cyclic mechanical strain alters the composition of differentiated intestinal cell populations. Specifically, we identify a strain-induced shift in the absorptive lineage towards a less mature state, with expansion of the population of early-stage enterocytes at the crypt-villus interface. This shift is associated with downregulation of transcriptional programs controlling enterocyte maturation within absorptive precursor populations. Our findings indicate that mechanical strain directs the maturation of the intestinal absorptive lineage, and highlight a role for mechanical forces in shaping intestinal epithelial composition and function.

cell biology↗

bioRxiv2025

E-cadherin mechanotransduction activates EGFR-ERK signaling in epithelial cells by inducing ADAM-mediated ligand shedding

The behavior of cells is governed by signals originating from their local environment, including mechanical forces that cells experience. Forces are transduced by mechanosensitive proteins, which can impinge on signaling cascades that are also activated by growth factor receptors upon ligand binding. We investigated the crosstalk between these mechanical and biochemical signals in the regulation of intracellular signaling networks in epithelial monolayers. Phosphoproteomic and transcriptomic analyses on epithelial monolayers subjected to mechanical strain revealed ERK signaling as a predominant strain-activated hub, initiated at the level of the upstream epidermal growth factor receptor (EGFR). Strain-induced EGFR-ERK signaling depends on mechanosensitive E-cadherin adhesions. Proximity labeling identified the metalloproteinase ADAM17, an enzyme that mediates shedding of soluble EGFR ligands, to be closely associated with E-cadherin. We developed a novel probe for monitoring ADAM-mediated shedding, which demonstrated that mechanical strain induced ADAM activation. Mechanically-induced ADAM activation was essential for mechanosensitive signaling from E-cadherin adhesions towards EGFR-ERK. Collectively, our data demonstrate that mechanical strain transduced by E-cadherin adhesion triggers the shedding of EGFR ligands that stimulate downstream downstream ERK activity. Our findings illustrate how mechanical signals and biochemical ligands can operate within a single, linear signaling cascade. Significance statementCells integrate different types of information that they receive from their local environment to regulate their behavior. This includes biochemical signals, such as growth factors binding to their dedicated receptor. Similarly, cells respond to mechanical forces that they are subjected to. Although biochemical and mechanical signals can elicit similar signaling responses in cells, the interplay between these types of signals is not well understood. Here we unveil that mechanical strain of epithelia modulates the activity of the EGFR-ERK signaling pathway by controlling the availability of growth factors that bind and activate EGFR. This finding demonstrates that biochemical and mechanical signals do not act in a segregated fashion, but rather can function in a linear cascade, shedding light on fundamental principles governing cellular regulation.

cell biology↗

bioRxiv2024

Mature tuft cell phenotypes are sequentially expressed along the intestinal crypt-villus axis following cytokine-induced tuft cell hyperplasia

Intestinal tuft cells are epithelial sentinels that trigger host defense upon detection of parasite-derived compounds. While representing interesting targets for immunomodulatory therapies in inflammation-driven intestinal diseases, their detailed functioning is poorly understood. Although two distinct intestinal tuft cell types have been described, we reveal common intermediary transcriptomes among tuft cells in mouse and human. Tuft cell-specific reporter knock-ins in organoids show that the two tuft types are sequentially expressed transcriptomic states that represent different maturation stages. Moreover, cytokines interleukin-4 and interleukin-13 only induce lineage specification to Nrep+ tuft-1 cells, while BMP and cholinergic signalling advance differentiation towards immune-related ChAT+ tuft-2 phenotypes. Functionally, both tuft cell states have chemosensory capacity and respond to stimuli like succinate, but reaction probability increases during tuft cell maturation. Our tuft type-specific reporters and optimized differentiation strategy in organoids provide an experimental platform to study the functioning of tuft cells and their unique chemosensory properties.

cell biology↗

bioRxiv2024

PIEZO-dependent mechano-sensing of the niche is essential for intestinal stem cell fate decision and maintenance

Stem cells continuously perceive and respond to various environmental signals to maintain homeostasis. In addition to biochemical factors, the stem cell niche is subjected to mechanical and physical cues. However, it remains unclear how stem cells can sense mechanical signals from their niche in vivo. Since intestinal stem cells constantly and directly face the external environment, we investigated the roles of mechano-sensing PIEZO ion channels in the gut stem cell niche. By employing mouse genetics and performing single-cell RNAseq analysis, we revealed the absolute requirement for PIEZO channels in intestinal stem cell (ISC) state dynamics and maintenance. In vivo measurement of basement membrane region stiffness demonstrated that ISCs reside in a more rigid microenvironment at the bottom of the crypt. Using 3D and 2D organoid systems combined with bioengineered substrates and a cell stretching device, we found that PIEZO channels are activated by high extracellular matrix stiffness and tissue tension to modulate ISC behavior. This study delineates the mechanistic cascade of PIEZO channel activation in ISCs from the upstream extracellular stimuli through the downstream signaling activation that coordinates stem cell fate decision and maintenance.

cell biology↗

bioRxiv2023

Mechanical regulation of cell fate transitions underlying colorectal cancer metastasis formation

Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site are devoid of Lgr5 expression. It is currently unknown how CRC cell fate transitions are regulated during the metastatic process and how tumor cells give rise to metastatic lesions despite being Lgr5neg. Here, we show that the reprogramming of disseminating CRC cells is driven by mechanical interactions with the Collagen I-rich interstitial matrix. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a fetal-like state. The fetal-like state is maintained after reaching the blood circulation and promotes metastasis-initiation of disseminated CRC cells in the liver. Our findings indicate a key contribution of mechanical signals in controlling cell fate transitions that underlie the metastatic potential of CRC, involving an interplay between different mechanosensitive mechanisms.

cancer biology↗