William H. Fleming, M.D., Ph.D.

Research interests

Normal hematopoiesis and the endothelium: Classical studies in embryology demonstrated the existence of the hemangioblast, a stem cell that can give rise to both hematopoiesis and blood vessels. We have shown that single hematopoietic stem cells (HSC) can gave rise to both hematopoietic and endothelial cell outcomes providing evidence for the existence of an adult hemangioblast. Human hematopoietic progenitor transplants also demonstrated donor derived endothelial cell outcomes. Additional studies revealed that endothelial cells could be derived from myelomonocytic progenitor cells and that bone marrow derived HSC had the potential to contribute to lymphatic endothelium. Current studies are evaluating the role of these hematopoietic cells in normal vascular homeostasis and tissue regeneration.

Endothelial cells and the hematopoietic microenvironment: The self-renewal and lineage-specific differentiation of the HSC is tightly regulated by the hematopoietic microenvironment. It is increasingly apparent that endothelial cells are a critical component of the microenvironment and we have recently shown that BMP4 regulates the hematopoietic stem cell niche. We have also demonstrated that endothelial cells generate signals that mediate the regeneration of hematopoietic stem cells following radiation injury. Ongoing studies are focused on determining the mechanisms responsible for hematopoietic regeneration.

Leukemia initiating cells and the microenvironment: We have recently begun to investigate the interaction between endothelial cells and leukemia initiating cells. Both in vitro and in vivo studies of human acute myelogenous leukemia (AML) indicate that these leukemia cells have a significant proangiogenic effect. Furthermore, vascular endothelium supports the growth and survival of primary AML. We are actively investigating the cross-talk between leukemia cells and the vascular microenvironment.

In summary, the functional interactions between vasculature and normal and leukemic hematopoietic stem cells represent a new area of investigation that has important implications for our understanding of both hematopoiesis and endothelial cell biology. Our ongoing studies are focused on determining the mechanisms responsible for regulating the cross talk between the hematopoietic and vascular systems.

Selected publications

  1. Smith S.M., Goldman D.C., Bailey A.S., Pfaffle D.L., Kreklywich C.N., Spencer D.B., Othieno F.A.,  Steblow D.N., Garcia J.V., Fleming W.H., Nelson J.A: G-CSF reactivates human cytomegalovirus in a latently infected humanized mouse model. (Cell Host & Microbe – In Press, 2010)
  2. Li B., Bailey A.S., Jiang S., Liu B., Goldman D.C., Fleming W.H.  Endothelial cells mediate the the regeneration of hematopoietic stem cells. Stem Cell Res. 4(1):17-24, 2010
  3. Goldman DC, Bailey AS, Pfaffle DL, Al Masri A, Christian JL, Fleming WH. BMP4 regulates the hematopoietic stem cell niche. Blood 114:4393-4401, 2009.
  4. Jiang S, Bailey AS, Goldman DC, Swain JR, Wong MH, Streeter PR, Fleming WH: Hematopoietic stem cells contribute to lymphatic endothelium. PLoS ONE. 3(11):e3812, 2008
  5. Bailey AS, Willenbring H, Jiang S, Anderson DA, Schroeder DA, Wong MH, Grompe M, Fleming WH: Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci USA 103:13156-13161, 2006
  6. Rizvi AZ, Swain JR, Bailey AS, Davies PS, Decker AD, Willenbring H,  Grompe M, Fleming WH, Wong MH: Bone marrow-derived cells regenerate intestinal epithelium by fusion with multipotent progenitors. Proc Natl Acad Sci USA 103:6321-6325, 2006.
  7. Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, Finegold M, Fleming WH, Grompe M: Myelomoncytic cells are sufficient for therapeutic cell fusion in liver. Nature Med. 10:744-748, 2004.
  8. Bailey AS, Jiang S, Afentoulis M, Baumann CI, Schroeder DA, Olson SB, Wong, MH, Fleming WH: Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood. 103:13-19, 2004.
  9. Jiang S, Walker L, Afentoulis M, Anderson DA, Jauron-Mills, L, Corless CL, Fleming, WH: Transplanted human bone marrow contributes to vascular endothelium. Proc Natl Acad Sci U S A. 101:16891-16896, 2004.
  10. Baumann CI, Bailey AS, Li W, Ferkowicz MJ, Yoder MC, Fleming WH: PECAM-1 is expressed on hematopoietic stem cells throughout ontogeny and identifies a population of erythroid progenitors. Blood. 104:1010-1016, 2004.