Regulation of the intestinal stem cell compartment after hematopoietic transplantation

Sloan-Kettering Inst Can Research, New York NY

Investigators

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Abstract

Intestinal injury is a major complication of allogeneic hematopoietic transplantation, limiting its wider use. The immune system plays a pivotal role in causing intestinal pathology in graft vs. host disease (GVHD) occurring post-transplant, but the immune system can also provide critical contributions to epithelial regeneration and in- testinal repair. We have found that immune-mediated interactions with the intestinal stem cell (ISC) compartment are important contributors to both the damage and regeneration occurring in the intestines in acute GVHD, and the previous funding period resulted in several impactful contributions to understanding immunologic effects on the ISC compartment after bone marrow transplantation (BMT), including that 1) the crypt base ISC compartment is the initial site of donor T cell infiltration within the intestines, where their overproduction of Interferon-g (IFNg) can directly induce Bax/Bak-dependent ISC apoptosis at high concentrations; and 2) Interleukin-(IL-)22 can di- rectly signal to ISCs, promoting their survival and regeneration after damage, and it can be administered thera- peutically post-BMT to promote thymic and intestinal recovery. IL-22 administration can also counteract toxicity from corticosteroids, which reduce ISC proliferation and epithelial regeneration. The experimental work from this project resulted in a multicenter clinical trial treating newly diagnosed gastrointestinal acute GVHD with recom- binant human IL-22. In this renewal, we propose to build upon this progress and conduct a mechanistic evalua- tion of immune-mediated and niche-driven epithelial regeneration in the context of allogeneic BMT. Our new preliminary data indicate profound transcriptomic changes in the ISC compartment in GVHD, identifying a novel pathway of IFNg/STAT1-mediated regulation of ISC c-MYC expression and epithelial regeneration. We believe this pathway induces ISC proliferation at low concentrations of IFNg, whereas high concentrations induce apoptosis. Our new data also indicate that Paneth cell loss may not be driving intestinal pathophysiology in GVHD, and other secretory epithelial cells may also produce growth factors for the niche. Utilizing our experience in ex vivo organoid modeling and ISC immunology, 3-D confocal imaging, and cytokine biology developed in the initial funding period, as well as newly developed approaches for epithelial transcriptomics, we propose to ex- plore these preliminary findings further by 1) investigating the importance of epithelial Myc expression post-BMT using a newly developed model of conditional Myc deletion, 2) dissecting IL-22 and IFNg’s distinct and overlap- ping JAK/STAT responses regulating the ISC compartment, and 3) ablating Paneth cells and other secretory lineage cells to determine their importance for ISC maintenance and epithelial regeneration after transplant. We will then build upon these insights to develop novel approaches manipulating epithelial JAK/STAT signaling and niche function to promote intestinal recovery. This renewal will thus pursue basic mechanisms of transplant biology, mucosal immunology, and stem cell research and extend them to translational investigations with the potential to improve clinical outcomes for transplant patients and others suffering from intestinal pathology.