A major focus of Dr. Abkowitz's is hematopoietic stem cells (HSC). HSC are the parent cells that establish and maintain blood cell production. HSC reside in anatomic niches within the marrow, are infrequent (< 1 per 10 5 marrow cells in mice, < 1 per 10 7 marrow cells in man), and their cell fate decisions depend on microenvironmental as well as intracellular signals. The laboratory uses several novel experimental techniques, including studies of mobilization and homing in parabiotic mice, to derive information about the number and behavior of HSC in vivo. In addition, in collaboration with Dr. Peter Guttorp, Department of Statistics, Dr. Abkowitz uses stochastic simulation and evolutionary analyses to estimate the mean rates of replication, differentiation, and apoptosis of HSC in mouse, cat, and non-human primate, and is developing strategies to extrapolate these results to man.
The laboratory also studies the molecular and cellular events that control red cell differentiation. Recently, Dr. Abkowitz identified, through expression cloning, a membrane transport protein (FLVCR) that is critical for the survival of the earliest morphologically-definable erythroid precursor, the proerythroblast, and demonstrated that it exports cytoplasmic heme. Heme is a critical component of cytochromes, catalases, glutathione peroxidase, hydroxylases, and nitric oxide synthase, as well as myoglobin and hemoglobin, and thus is necessary for the survival and integrity of all aerobic cells. It is also a transcriptional and translational regulator of globin synthesis (and thus erythropoiesis). However, excess free heme is toxic, leading to lipid peroxidation, membrane instability and cell apoptosis, so that a tight balance between heme synthesis and heme use is required. Flvcr-/- mice die during embyrogenesis due to a failure in definitive erythropoiesis and neonatally-deleted Flvcr flox/flox;Mx-cre mice develop red cell aplasia. It also appears that Flvcr is important in placenta, liver, duodenum, and macrophage, and may serve to protect these non-erythroid tissues from high intercellular heme flux and/or facilitate heme trafficking and systemic iron hemostasis. The laboratory is using genetic and physologic approaches to investigate the functions of Flvcr and its role a modifier of disease phenotype. Dr. Abkowitz's laboratory is also interested in understanding the coordinate molecular regulation of heme and globin synthesis as primary erythroid progenitor cells mature.
Abkowitz JL, Catlin SN, and Guttorp P: Evidence that hematopoiesis may be stochastic in vivo. Nature Medicine 2:190-197, 1996.
Abkowitz JL, Persik MT, Shelton GH, Catlin SN, Guttorp P, and Kiklevich JV: An X-chromosome gene regulates hematopoietic stem cell kinetics. Proc. Natl. Acad. Sci. USA 85:3862-3866, 1998.
Kennedy DW and Abkowitz JL: Mature monocytic cells enter tissues and engraft. Proc. Natl. Acad. Sci. USA 95:4944-14949, 1998.
Abkowitz JL, Catlin SN, SN, McCallie MT, Guttorp P: Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100:2665-2667, 2002.
Abkowitz JL, Robinson AE, Kale S, Long MW, Chen J: Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood 102:1249-1253, 2003.
Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL: Identification of a human heme exporter that is essential for erythropoiesis. Cell 118:757-766, 2004.