BMP Signaling Promotes Immune Cell Differentiation in Human Intestinal Organoids

Project Abstract Human pluripotent stem cell (hPSC) derived human intestinal organoids (HIOs) are a powerful model since they possess many lineages, including epithelium, smooth muscle, neurons, and endothelial cells; however, HIOs lack immune populations, which are key to studying the development and maturation of the intestine. Since early HIOs possess mesoderm, I tested the hypothesis that this population may respond to cues, such as BMP signaling, that induce immune cell differentiation. Preliminary data supports a role for BMP signaling as an inductive cue for CD45+ immune cells within small intestinal HIOs. This proposal will test the hypothesis that early HIOs retain plasticity soon after intestinal patterning and have mesenchyme-specific responses to BMP signaling, which leads to differentiation of the mesenchyme into hemogenic endothelium that will further differentiate into functional immune lineages. I aim to interrogate the mechanism by which BMP4 induces immune-like cells, through a hemogenic endothelium intermediate, in HIOs, including the cell intermediates required for immune cell differentiation. Secondly, I aim to investigate the lineages of immune cells present and functionally evaluate the immune-like cells in the HIOs.