Bradley Blaser, MD
Bradley W. Blaser, MD
Dana-Farber Cancer Institute
Regulation of Hematopoietic Stem Cell Engraftment by the Endothelial Cell Niche
Grant Term: July 1, 2014 – June 30, 2015
The aim of our work is to discover novel regulators of blood stem cell engraftment in the developing zebrafifish. We have performed a genetic screen to identify secreted factors that may be involved in this process. Since the inception of this grant, we have cloned and tested 57 such factors and have found two hits, CXCR1 and WNT5A. CXCR1 is a receptor for the chemokine IL-8. Chemokines, or "chemoattractant cytokines" are growth factors that regulate cellular growth and motility. CXCR1/IL-8 is well known as a mature immune cell signaling pathway, yet its role in hematopoiesis, or the growth and behavior of blood stem cells is unknown. We are currently working to understand the cellular mechanisms by which CXCR1 and IL-8 mediate stem cell interactions with the surrounding microenvironment.
In addition, we are continuing the genetic screen to identify more novel mechanisms of stem cell engraftment. Detailed mechanistic studies and translational experiments will be performed as we identify more of these factors.
January 23, 2017 Update
Dr. Bradley Blaser received his PhD in Immunology in 2006 and his MD in 2008 at the Ohio State University. From 2008-2011 he completed an internship and residency in Internal Medicine at Brigham and Women's Hospital in Boston, and from 2011 to 2012 he was a Clinical Fellow in Hematology and Oncology at Dana-Farber Cancer Institute. In 2012, he began a Postdoctoral Research Fellowship in the laboratory of Dr. Leonard Zon at Boston Children's Hospital. Currently he holds the position of Instructor of Medicine at Harvard Medical School and is also an attending physician in the Stem Cell Transplant program at Dana-Farber Cancer Institute.
The aim of Dr. Blaser's Young Investigator Award project, entitled Regulation of Hematopoietic Stem Cell Engraftment by the Endothelial Cell Niche, was to identify novel factors involved in the mechanism by which hematopoietic (blood-forming) stem cells interact with their supporting cells, or niche, in the embryonic zebrafish. Hematopoietic stem cell transplantation is a potentially curative therapy for both adult and pediatric leukemia and lymphoma. The safety of this procedure and the ability of it to effectively cure these cancers is compromised by many factors, including the immunologic differences between donor and recipient, the aggressive biology of cancer cells remaining in the patient immediately prior to transplant as well as the toxicity of the radiation and chemotherapy necessary to "condition" the recipient to receive the transplant. Finding less toxic and more effective ways to help the donor stem cells find their way from the recipient bloodstream to their niche in the bone marrow would be a major advance in this field.
The developing zebrafish has many characteristics that make it an ideal experimental model to study how blood stem cells enter, interact with, and exit their niche. Most important of these is that beginning at 3 days post-fertilization, newly formed blood stem cells leave the circulation and enter a loose plexus of blood vessels in the tail of the fish called the caudal hematopoietic territory (CHT). In terms of structure and function, the CHT resembles the human bone marrow under conditions of stress, as can be observed in stem cell transplant recipients. In the work funded by the Strike 3 Foundation and the Conquer Cancer Foundation, Dr. Blaser and his team used a genetic screen to identify a gene, CXCR1, that is expressed in the zebrafish CHT that is important for regulating the growth and supportive functions of this special niche. Enhancing the function of CXCR1 caused the niche to expand and allowed it to support about 50% more stem cells than an unmodified niche. Conversely, blocking the function of CXCR1 reduced the size of the niche and the numbers of stem cells it could hold. This work is currently under peer-review for publication.
Dr. Blaser and his team believe that modulating the function of CXCR1 and other genes expressed within the bone marrow niche might provide a way to decrease the time necessary for stem cell transplant recipients to regain normal blood cell numbers and perhaps even to improve the ability of these cells to fight infection and prevent relapse of their cancer. His ongoing work is aimed at identifying these novel factors and in the future he hopes to translate these basic findings into the clinic.
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