The intestinal epithelium maintains a remarkable balance between proliferation and differentiation despite rapid cellular turnover. A central challenge is to elucidate mechanisms required for robust control of tissue renewal. Opposing WNT and BMP signaling is essential in establishing epithelial homeostasis. However, it has been difficult to disentangle contributions from multiple sources of morphogen signals in the tissue. Here, to dissect epithelial-autonomous morphogenic signaling circuits, we developed an enteroid monolayer culture system that recapitulates four key properties of the intestinal epithelium, namely the ability to maintain proliferative and differentiated zones, self-renew, polarize, and generate major intestinal cell types. We systematically perturb intrinsic and extrinsic sources of WNT and BMP signals to reveal a core morphogenic circuit that controls proliferation, tissue organization, and cell fate. Our work demonstrates the ability of intestinal epithelium, even in the absence of 3D tissue architecture, to control its own growth and organization through morphogen-mediated feedback.

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Renewing tissues have the remarkable ability to maintain both proliferative progenitor and specialized mature cell types at consistent ratios. How are complex milieus of microenvironmental signals interpreted to coordinate tissue cell-type composition? Here, we develop a high-throughput approach, combining organoid technology, combinatorial perturbations, and quantitative imaging to address these questions in the context of the intestinal epithelium. We find that changes in proliferation of transit-amplifying (TA) cells, but not Lgr5 + stem cells, alters the composition of mature secretory and absorptive cell-types in organoids and in vivo. The link between TA proliferation and mature fate bias arises from differential amplification of secretory and absorptive progenitor cells. Further, TA cells have a distinct pattern of regulation from other epithelial celltypes that stems, in part, from signal integration via the MEK-Erk pathway and paracrine BMP production. These results demonstrate that TA cells, a feature of many renewing tissues, play a critical role in converting complex microenvironmental signals into changes in cell-type composition.

The epithelial lining of the human intestine is a prime example of tight homeostatic control of cell proliferation, organization and fate determination. As a mechanism for dealing with constant mechanical, chemical and pathogen‐derived insults, the epithelium is in constant turnover, completely renewing every four days. Amazingly, this active process produces multiple cell types at just the right ratios and locations throughout our life span. Failure of this exquisite control is the basis for diseases including Crohn's disease, ulcerative colitis, and cancers of the esophagus, stomach, small and large intestine.A central challenge is to elucidate mechanisms required for robust control of tissue renewal. Opposing WNT and BMP signaling is essential in establishing epithelial homeostasis. However, it has been difficult to disentangle contributions from multiple sources of morphogenic signals in the tissue. Here, to dissect epithelial‐autonomous morphogenic signaling circuits, we developed a planar enteroid intestinal culture system that recapitulates key properties of the intestinal epithelium, specifically the ability to: maintain proliferative and differentiated zones, self‐renew, polarize and generate major intestinal cell types. We systematically perturb intrinsic and extrinsic sources of WNT and BMP signals to reveal a core morphogenic circuit that controls proliferation, tissue organization and cell fate. Our work demonstrates the ability of intestinal epithelium, even in the absence of 3D tissue architecture, to control its own growth and organization through morphogen‐mediated feedback.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.