Ofer, R. | Search bioRxiv

bioRxiv2025

A Spatial and Temporal Transcriptomic Atlas of Mouse Intestinal Regeneration

Background & AimsThe intestinal epithelium exhibits a remarkable capacity for regeneration following injury. However, the spatial and temporal dynamics of the injury-repair cycle remain incompletely understood. MethodsWe employ spatial transcriptomics to create an atlas of the damage and repair response to ionizing radiation in the mouse intestine. We map molecular events driving epithelial recovery over a six-day period and 23 biological samples, spanning the early apoptotic response to tissue remodeling and repair. ResultsThe datasets capture mRNA of 19,042 genes in [~]26 million bins at 2{micro}m resolution. Analysis revealed transcriptional patterns and niche signals that would remain undetected in bulk or single-cell approaches, including a non-random activation of interferon-target genes. Temporal shifts in cytokine and growth factor gene expression, particularly in the crypt and lower villus regions, corroborate published studies and reveal new predictions of the mechanisms governing intestinal healing. Global transcriptional upregulation was observed in the regenerating epithelium, suggesting hypertranscription is a hallmark of intestinal repair. Furthermore, we observe altered cellular differentiation trajectories and villus patterning at the early stages of regeneration. ConclusionsTogether, our work provides a detailed spatiotemporal map of intestinal regeneration at subcellular resolution and nearly whole-genome scale. These data lay the groundwork for future discoveries and therapeutic strategies to enhance epithelial repair in inflammatory bowel diseases and other gastrointestinal pathologies or in response to side-effects of cancer therapies.

molecular biology↗

bioRxiv2023

Zoledronic acid improves bone quality and muscle function in a high bone turnover state

SUMMARYZoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGF{beta} release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease. Context and significanceTGF{beta} is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGF{beta} causes several bone disorders and skeletal muscle weakness. Reducing excess TGF{beta} release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acids benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.

cancer biology↗