Implementation of a high-content screen in 3D intestinal organoids to identify conceptually novel drugs actively stimulating regeneration of the colonic epithelium. The epithelium constitutes a vital barrier against luminal bacteria as loss of barrier integrity causes bacterial influx into underlying tissues. In UC patients, this initiates a viscous cycle of immune-mediated epithelial destruction, which can be alleviated by enhanced epithelial healing.
Impact
The work is expected to identify novel compounds actively stimulating epithelial regeneration to facilitate wound healing and barrier restoration in patients suffering from UC. These patients currently only receive immunosuppressive drugs as a symptomatic treatment. Complementing this with stimulation of epithelial healing can likely solve the underlying cause of disease flares, improving quality of life for patients suffering from this stigmatizing disease.
reNEW research
We are optimizing organoid growth conditions and developing reporter lines and antibody-based strategies to discriminate the range of phenotypes expected to unfold in our high-content screen. In parallel, we are implementing automated image-analysis pipelines to discriminate organoid states using morphological parameters and quantification of cell type frequencies guided by our reporters and antibody stainings.
Image description
The image displays a human colonic organoid stained in 3D for the membrane marker E-Cadherin (green), the actin cytoskeleton (cyan) and the goblet cell marker TFF3 (magma). During normal conditions, organoids display an elaborate budding morphology and presence of large numbers of goblet cells. When stimulating the organoids to enter a regenerative state, the morphology is dramatically altered towards a spherical appearance with a marked loss of differentiation.
Credits
Hjalte List Larsen, Assistant Professor, Jensen Lab, reNEW Copenhagen.
