bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.01.13.523825

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration

Chen, L.·Dupre, A.·Qiu, X.·Pellon-Cardenas, O.·Walton, K. D.·Wang, J.·Perekatt, A. O.·Hu, W.·Spence, J. R.·Verzi, M. P.
View original source ↗Export metadata ↓

Abstract

The adult gut epithelium has a remarkable ability to recover from damage. To achieve cellular therapies aimed at restoring and/or replacing defective gastrointestinal tissue, it is important to understand the natural mechanisms of tissue regeneration. We employed a combination of high throughput sequencing approaches, mouse genetic models, and murine and human organoid models, and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. Depletion of macrophages or genetic disruption of TGFB-signaling significantly impaired the regenerative response following irradiation. Murine intestinal regeneration is also characterized by a process where a fetal transcriptional signature is induced during repair. In organoid culture, TGFB1-treatment was necessary and sufficient to induce a transcriptomic shift to the fetal-like/regenerative state. The regenerative response was enhanced by the function of mesenchymal cells, which are also primed for regeneration by TGFB1. Mechanistically, integration of ATAC-seq, scRNA-seq, and ChIP-seq suggest that a regenerative YAP-SOX9 transcriptional circuit is activated in epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for the application of the TGFB-induced regenerative circuit in cellular therapy. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/523825v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@147f3b7org.highwire.dtl.DTLVardef@d1a64dorg.highwire.dtl.DTLVardef@1fd0dc0org.highwire.dtl.DTLVardef@91f7d8_HPS_FORMAT_FIGEXP M_FIG C_FIG

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Chen, L., Dupre, A., Qiu, X., Pellon-Cardenas, O., Walton, K. D., Wang, J., Perekatt, A. O., Hu, W., Spence, J. R., Verzi, M. P.. 2023-01-13. TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration. https://doi.org/10.1101/2023.01.13.523825

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

KEEP EXPLORING

Related preprints

bioRxiv2026

High-content screening identifies FDA-approved activators of mitophagy

Mitochondrial diseases are highly heterogeneous disorders caused by defects in oxidative phosphorylation, for which only limited therapeutic options are available. The elimination of dysfunctional mitochondria via mitophagy activation is an attractive strategy to treat several mitochondrial diseases, irrespective of the underlying genetic defect. To identify pharmacological activators of this pathway, we performed a high-content screening of 1,971 FDA-approved compounds using cellular reporters of TFEB nuclear translocation and mitophagy. This screening identified 294 compounds that promoted TFEB translocation, nine of which increased the number of mitolysosomes without compromising cell viability or damaging mitochondria. Among the selected compounds, Meptazinol and Ponatinib emerged as the top-ranked mitophagy inducers in fibroblasts from patients with complex I and IV deficiency, respectively, and were prioritised for further characterisation. However, they did not rescue the bioenergetic defect, suggesting that the stimulation of mitophagy per se is not sufficient to ameliorate the OXPHOS defect in mitochondrial diseases. Overall, our findings establish a scalable platform for the identification of pharmacological activators of TFEB and identify candidate compounds for therapeutic modulation of mitophagy.

cell biology↗
bioRxiv2026

A LOV-domain photoreceptor mediates phototaxis in brown algae

Phototaxis enables motile cells to navigate light environments and plays a critical role in survival and reproduction across diverse eukaryotic lineages. This ability has evolved independently through distinct photoreceptor systems. Yet, the molecular mechanisms underlying phototaxis remain poorly understood in many major eukaryotic lineages, including stramenopiles. Here, combining functional genetics, cell biology and evolutionary analyses, we identify Helmchrome (HELM), a LOV-domain protein required for phototaxis in the brown alga Ectocarpus. HELM localizes to the posterior flagellum and is responsible for the characteristic flavin-associated fluorescence of brown algal gametes. Loss of HELM abolishes phototactic accumulation and directional orientation without affecting basal motility or fertilization, demonstrating its specific requirement for light-directed movement. Phylogenetic analyses reveal that HELM-like proteins are distributed across diverse stramenopile lineages and that their domain architecture evolved through repeated duplication of an ancestral RGS-LOV module. Our findings identify HELM as a key component of the light-sensing machinery in brown algae, provide a molecular explanation for the long-standing observation of flagellar flavin fluorescence, and reveal a distinct phototaxis system that expands the known diversity of eukaryotic light-sensing mechanisms.

cell biology↗
bioRxiv2026

A distinct chondrogenic progenitor population from human umbilical cord derived mesenchymal stromal cells for osteoarthritis therapy

Stem cell-based cartilage regeneration remains constrained by functional heterogeneity and phenotypic drift in conventional cell sources, compromising durable structural repair. Human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) represent an accessible, off-the-shelf cell source; however, their broad clinical utility is hampered by cellular heterogeneity, leaving the key chondrogenic subpopulation responsible for cartilage repair unresolved. By integrating single-cell transcriptomics with functional assays, we identified and prospectively isolated a distinct, highly expandable subpopulation of skeletal stem cell-like progenitors (U-CPCs) from the human umbilical cord, establishing an extra-skeletal cell source uniquely primed for joint restoration. Single-cell transcriptomics reveal their inherent regulatory landscape, uncovering a distinct transcriptional state uniquely primed for chondrogenesis. In comparison with conventional stem cells and other tissue-derived SSC-like populations (from umbilical cord, bone marrow, adipose tissue, and dental pulp), U-CPCs exhibit a markedly enhanced chondrogenic capacity. In both a mouse cartilage injury model and a rat osteoarthritis model, the administration of U-CPCs effectively mitigates joint degeneration and drives the restoration of a structurally sound, hyaline-like matrix. Mechanistically, U-CPCs secrete extracellular vesicles enriched with microRNA Let-7a-5p, which specifically modulates DUSP7/MAPK/ERK signaling in recipient chondrocytes, thereby restoring extracellular matrix homeostasis and promoting cartilage repair. By characterizing these specialized extra-skeletal progenitors and elucidating both their intrinsic chondrogenic priming and paracrine regulation of host tissue, this study establishes U-CPCs as a robust, lineage-restricted cellular source for osteoarthritis therapy.

cell biology↗