Understanding hematopoietic stem cell dysfunction in refractory Crohn's disease

Despite an unprecedented growth in Crohn's disease (CD) therapies it has remained consistent that each new therapy is less effective for patients that failed a previous therapy leaving many patients refractory to treatment. While CD therapies seemingly encompass distinct therapeutic mechanisms, all target the inflammatory response supporting that medically refractory CD involves mechanisms not directly related to inflammation. The near universal success of autologous stem cell transplantation (SCT) in refractory CD provides a rare cohort to understand therapeutic mechanisms that exist outside of the traditional CD treatment paradigm. In our study of CD patients that received a SCT we strengthened previous associations between inflammatory macrophages and refractory disease but further suggested a refractory phenotype is acquired through dysfunction of hematopoietic stem cells (HSC) and progenitors that reinforce differentiation of aberrant myeloid cells unable to support intestinal healing and rendering immunotherapy ineffective. As such, the central goal of this proposal is to understand differences in hematopoietic progenitors associated with refractory CD and how hematopoietic progenitor dysfunction determines clinical outcomes. This proposal will advance our understanding of CD therapeutic mechanisms through (Aim 1) profiling of HSC populations associated with refractory CD and (Aim 2) characterizing HSC functions associated with refractory CD and therapeutic outcomes. In Aim 3 we will explore a poorly defined intestinal HSC niche important to our long-term goal of understanding how myeloid progenitors support intestinal populations that reinforce refractory disease or promote healing.