Manipulating the Stem Cell Epigenome to Improve Bone Marrow Transplantation

点击翻译按钮获取中文摘要

ABSTRACT Bone marrow transplantation (BMT) is the best-established stem cell therapy, and has been used successfully in clinical settings for almost 50 years. However, identifying sources of appropriate donor material for BMT continues to be a limiting factor for many adult patients. Umbilical cord blood (UCB) has become an increasingly popular donor source because the hematopoietic cells from newborn babies are immunologically more naïve. This reduces the risk of graft-versus-host-disease (GvHD), and therefore the patient and donor do not have to be as immunologically compatible. UCB has extended patient access to BMT, especially for patients of racial and ethnic minorities. Despite multiple advantages of UCB transplant, it is associated with delayed engraftment and immune reconstitution, leading to a greater risk of infections and graft reject as compared to bone marrow or peripheral blood grafts from adult donors. This is primarily related to the lower content of hematopoietic stem cells (HSCs), the functional units of long-term hematopoietic repopulation in BMT, within individual cord blood units. These caveats have limited the application of UCB transplantation. There are intense efforts to expand UCB HSC numbers or increase their potency ex vivo, but these studies have been largely unsuccessful. Here, we propose a novel method to resolve this long-standing problem. In murine models, we identified a mechanism that prevents chromatin-mediated silencing of HSC self-renewal genes by antagonizing the epigenetic regulator JARID2, which recruits Polycomb Repressive Complex 2 (PRC2) to catalyze the repressive histone modification of H3K27me3. Here, we will leverage these results to determine if transient inhibition of JARID2 can be used to increase the number of transplantable HSCs ex vivo, and improve BMT. Specifically, we hypothesize that JARID2 inhibition will prevent PRC2-mediated epigenetic repression of self-renewal gene expression programs, thereby expanding the pool of cells with functional repopulation potential. We will formally investigate this strategy in the following Specific Aim:  Determine if inhibition of JARID2 can expand functional repopulating cells for bone marrow transplant and define the mechanisms There are three prongs to our approach; (A) Determine if transient inhibition of JARID2 can expand the pool of functional HSCs, (B) Identify the protein domains of JARID2 required for PRC2-mediated repression of HSC self-renewal genes, and (C) Identify trans-activating factors that regulate JARID2 expression for translational exploitation. The SHINE-II mechanism (PAS-15-168) is dedicated to supporting new research directions in their early stages. Consistent with this goal, translational BMT research is a completely new area of study for our lab. But with our experience in epigenetic regulation of HSCs and access to collaborative expertise, we are poised to make novel contributions to this significant clinical problem. Achievement of our research objectives will provide the basis for future high-impact translational research, consistent with the goals of PAS-15-168.