Regulation of Hematopoietic Stem Cell Engraftment by the Endothelial Cell Niche
Allogeneic hematopoietic stem cell transplantation (HSCT), or bone marrow transplantation, is the most aggressive treatment available for children with high-risk or relapsed leukemia. Despite this aggressive treatment, half of the children who receive HSCT will ultimately die of their disease or the side effects of transplantation. Consequently it is important for us to identify new ways to improve the safety and efficacy of HSCT.
Children who receive allogeneic HSCT are treated with high doses of chemotherapy and radiation followed by intravenous infusion of hematopoietic stem cells (HSCs) from another individual. Circulating HSCs home to the bone marrow, engraft within a microenvironment formed by cells lining the marrow blood vessels, and then establish a new blood system. HSCs are guided to the microenvironment by chemoattractants and cellular adhesion molecules. Once there, the HSCs compete for growth factors and other resources with residual leukemia cells that have survived the conditioning regimen.
Using a genetic screen in the developing zebrafish, I have identified one molecule which is important for normal HSC engraftment. This proposal aims to understand the biology of this factor and to identify other secreted growth factors and chemoattractants that the microenvironment uses to regulate the activity of HSCs. Secreted factors are attractive candidates for drug development and may provide the key to improving outcomes for children who receive HSCT for high-risk leukemia. Promising candidates will be carried forward for additional translational and clinical studies in concert with the Boston Children's Hospital Stem Cell Transplantation Program.
2017 Project Update
Hematopoietic stem cell transplantation is a potentially curative therapy for children with high risk and relapsed cancers, especially leukemia. Patients who undergo stem cell transplantation receive high doses of chemotherapy and/or radiation to eliminate residual leukemia cells and allow a space for the new donor-derived stem cells to engraft within the bone marrow "niche". This aggressive therapy comes with a host of significant side effects. These range from organ damage related to the toxicity of the chemotherapy and radiation, prolonged mucositis (breakdown of the lining of the mouth and gut) and risk of infection prior to engraftment of the donor stem cells, as well as long term immune deficiency and risk of opportunistic infections. Improving the efficiency of donor stem cell engraftment may make it possible to reduce the intensity of the conditioning regimens and to shorten the period of immune deficiency. Improving the efficiency of stem cell engraftment requires a deep understanding of how these cells exit the bloodstream and enter the hematopoietic niche within the bone marrow. The niche is composed of many cell types including endothelial cells (blood vessel lining cells), stromal cells (supportive cells), as well as nerve cells, fat cells and other immune cells. An emerging body of literature is showing that stem cells use the same types of signaling pathways to interact with the niche in normal development and during engraftment after transplantation. I have taken advantage of the developing zebrafish as a model of stem cell engraftment to identify molecules that may be important for interactions between stem cells and endothelial cells during this process. Using a genetic screen, I found that two molecules -- cxcl8 and its receptor, cxcr1, are important signals supporting HSC engraftment within this niche. These molecules have long been known to be important factors guiding mature white blood cells to the site of infection, yet the mechanisms by which hematopoietic stem cells use these factors was unknown. The work we have performed with the support of ALSF has shown the following: cxcl8 and cxcr1 are expressed within the endothelial cell niche and are induced by chemicals known to play a role in tissue repair, as occurs after the administration of chemotherapy. Cxcl8/cxcr1 signaling causes the niche to expand and to express other molecules that help stem cells adhere within the niche. These signals allow more room for stem cells to enter the niche, help them stay longer and allow more time for cell divisions to occur. Taken together, these findings identify cxcl8/cxcr1 as a positive regulator of stem cell engraftment and a potential therapeutic target to help improve engraftment in children who undergo hematopoietic stem cell transplantation.