Biology subjects

Martin-Alonso, M.

Publications and source records attributed to Martin-Alonso, M..

5 recordsLinked to original sources

bioRxiv2026

Prostaglandin E2 facilitates reciprocal crosstalk between intestinal smooth muscle tissue and epithelium in tumor development

Colorectal cancer arises from intestinal epithelial cells and is driven by the accumulation of aberrant signaling events that disrupt intestinal stem cell (ISC) homeostasis. While stromal regulation of the ISC niche is increasingly recognized, the contribution of the underlying/adjacent smooth muscle tissue (SMT) remains poorly characterized. In particular, the potential crosstalk between normal or tumoral epithelium and the SMT is largely unexplored. Here, we investigate the ability of the SMT in modulating normal and tumorigenic epithelial biology, and the impact of the tumoral epithelium on the underlying SMT. Mechanistically, by using imaging analyses, transcriptomics, and mass spectrometry, we identify the SMT-derived factor Prostaglandin E2 (PGE2) as the key driver of epithelial dedifferentiation, promoting YAP transcriptional activation, organoid enlargement, and spheroid morphology in intestinal epithelial organoids following SMT supernatant exposure. Conversely, we show that non-invasive tumoral epithelium induces significant changes in the underlying SMT. Tumor-associated SMT shows structural remodeling, inflammation, and reduced muscle fitness. Furthermore, we detected increased prostaglandin signaling, including upregulation of PGE2 synthase Ptgs1 (COX1), in the SMT underneath the epithelial tumor. Our results reveal a communication between the tumoral epithelium and the underlying SMT prior to metastasis, which could be a facilitating step for tumoral extramural progression. Taken together, these findings highlight a novel tumor-stroma interaction.

Molecular Biology↗

bioRxiv2023

Postnatal intestinal epithelial maturation by LSD1 controls the small intestinal immune cell composition independently from the microbiota

Postnatal development of the gastrointestinal tract involves the establishment of the commensal microbiota, maturation of the intestinal epithelium, and the acquisition of immune tolerance via a balanced immune cell composition. While studies have uncovered an interplay between the commensal microbiota and immune system development, less is known about the role of the maturing epithelium. Here, we comprehensively show that intestinal-epithelial intrinsic expression of lysine-specific demethylase 1A (LSD1) is necessary for the postnatal maturation of intestinal epithelium as well as maintaining this developed epithelial state in adulthood. Although the stool microbiome was altered in animals with an intestinal-epithelial specific deletion of Lsd1, by depleting the microbial component using antibiotics, we found that the cellular state and number of certain immune cell types were dependent on maturation of the epithelium. We found plasma cells, innate lymphoid cells (ILCs), and a specific myeloid population to be depending on epithelial LSD1 expression. We propose that LSD1 controls the expression of epithelial-derived chemokines, such as Cxcl16, and this is a mode of action for this epithelial-immune cell interplay. For example, we show that LSD1-mediated epithelial-intrinsic CXCL16 controls the number of local ILC2s but not ILC3s. Together, our findings suggest that the maturing epithelium plays a dominant role in regulating the local immune cell composition, thereby contributing to gut homeostasis.

immunology↗

bioRxiv2023

Mmp17-deficient mice exhibit heightened goblet cell effector expression in the colon and increased resistance to chronic Trichuris muris infection

Intestinal epithelial homeostasis is maintained by intrinsic and extrinsic signals. The extrinsic signals include those provided by mesenchymal cell populations that surround intestinal crypts and is further facilitated by the extracellular matrix (ECM), which is modulated by proteases such as matrix metalloproteinases (MMPs). Extrinsic signals ensure an appropriate balance between intestinal epithelial proliferation and differentiation. This study explores the role of MMP17, which is expressed by mesenchymal cells, in intestinal homeostasis and during immunity to infection. Mice lacking MMP17 expressed high levels of goblet-cell associated genes, such as CLCA1 and RELM-{beta}, which are normally associated with immune responses to infection. Nevertheless, Mmp17 KO mice did not have altered resistance during a bacterial Citrobacter rodentium infection. However, when challenged with a low dose of the helminth Trichuris muris, Mmp17 KO mice had increased resistance, without a clear role for an altered immune response during infection. Mechanistically, we did not find changes in traditional modulators of goblet cell effectors such as the NOTCH pathway or specific cytokines. Instead, we found elevated BMP signaling in Mmp17 KO mouse large intestinal crypts that we propose to alter the goblet cell maturation state. Together, our data suggests that MMP17 extrinsically alters the goblet cell maturation state via a BMP signaling axis, which is sufficient to alter clearance in a helminth infection model.

immunology↗

bioRxiv2020

Smooth muscle-specific MMP17 (MT4-MMP) defines the intestinal ECM niche

Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.

cell biology↗

bioRxiv2020

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that Lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 represses genes that are normally expressed in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and indeed, we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium towards a reparative state.

developmental biology↗