Goyne, J. M. | bioRxiv Science

bioRxiv2023

Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis.

Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist Gremlin 1 (Grem1) marks a novel chondrogenic progenitor (CP) cell population in the articular surface that generates joint cartilage and subchondral bone during development and adulthood. Notably, this CP population is depleted in injury-induced OA, and with age. OA is also induced by toxin-mediated ablation of Grem1 CP cells in young mice. Transcriptomic analysis and functional modelling in mice revealed articular surface Grem1-lineage cells are dependent on Foxo1; ablation of Foxo1 in Grem1-lineage cells led to early OA. This analysis identified FGFR3 signalling as a therapeutic target, and injection of its activator, FGF18, caused proliferation of Grem1-lineage CP cells, increased cartilage thickness, and reduced OA pathology. We propose that OA arises from the loss of CP cells at the articular surface secondary to an imbalance in progenitor cell homeostasis and present a new progenitor population as a locus for OA therapy.

cell biology↗

bioRxiv2021

Engineered bacteria detect tumor DNA in vivo

Advances in bacterial engineering have catalysed the development of living cell diagnostics and therapeutics1-3, including microbes that respond to gut inflammation4, intestinal bleeding5, pathogens6 and hypoxic tumors7. Bacteria can access the entire gastrointestinal tract8 to produce outputs measured in stool4 or urine7. Cellular memory, such as bistable switches4,9,10 or genomic rearrangements11, allows bacteria to store information over time. However, living biosensors have not yet been engineered to detect specific DNA sequences or mutations from outside the cell. Here, we engineer naturally competent Acinetobacter baylyi to detect donor DNA from the genomes of colorectal cancer (CRC) cells, organoids and tumors. We characterize the functionality of the biosensors in vitro with co-culture assays and then validate in vivo with sensor bacteria delivered to mice harboring colorectal tumors. We observe horizontal gene transfer from the tumor to the sensor bacteria in our mouse model of CRC. The sensor bacteria achieved 100% discrimination between mice with and without CRC. This Cellular Assay of Targeted, CRISPR-discriminated Horizontal gene transfer (CATCH), establishes a framework for biosensing of mutations or organisms within environments that are difficult to sample, among many other potential applications. Furthermore, the platform could be readily expanded to include production and delivery of antibiotic or antineoplastic therapeutic payloads at the detection site.

synthetic biology↗