Education:
BSc 1995 Molecular Biology - The University of Edinburgh, UK
PhD 1999 Virology - Imperial College School of Medicine, UK
Postdoctoral Research Fellowship:
1999-2003 Massachusetts General Hospital, Harvard Medical School, Boston, MA
Started at USC: 2007
Research Topics: Stem Cell Biology
Research Description
In the stem cell niche, neighboring subsets of cells and extracellular substrates house stem cells and provide specialized functions to modulate stem cell self renewal and progeny production in vivo. Therefore, understanding the microenvironmental niche and the intracellular signals that allow for expansion of the stem cells during development or disease settings will assist in the development of hematopoietic stem cell (HSC) based therapies. Currently my research is focused on three important aspects of HSC-niche biology.
1. Identifying the Components of the HSC Niche.
Previously we examined the role of the osteoblasts in the bone marrow microenvironment in vivo. Using mice genetically altered with osteoblast specific, activated parathyroid hormone/parathyroid hormone related peptide receptor, we demonstrated that stimulated osteoblastic cells were increased in number, produced high levels of the Notch ligand, Jagged1, and supported an increase in the number of HSCs with evidence of Notch1 activation in stem cells in vivo. However, cells of the osteoblastic lineage are probably only one of the key components of the HSC niche. Currently our research is aimed at examining other components of the HSC niche, as well as identifying the exact location of the HSC niche in vivo. By localizing and identifying the stem cells in the niche, we hope to be able to identify other instructive cues from the microenvironment in terms of the cellular interactions, growth factors or matrix molecules that influence the stem cells.
2. HSC Lodgment at the Endosteal Niche.
During both mammalian ontogeny and stem cell transplantation, HSCs in the peripheral circulation will ultimately home to and engraft in the correct microenvironmental niche in the bone marrow. However, the exact mechanism by which the stem cells recognize and lodge in the bone marrow niche is not known. We examined mice engineered to be deficient in the calcium sensing receptor (CaR-/-) and demonstrated primitive cells in the circulation and spleen, but impaired bone marrow localization of HSCs. CaR-/- fetal liver HSCs were normal in number and function, but were defective in establishing effective engraftment, specifically in the bone marrow endosteal niche. These studies demonstrated that an increased concentration of the bone mineral calcium may dictate the specific engraftment of HSCs in the bone marrow endosteal niche. We are continuing to examine this model system as a means to identify the specific mediators of stem cell retention in the niche.
3. HSC Migration to the Niche
While the microenvironment that surrounds stem cells defines the niche, the mechanisms by which the stem cells home to the bone marrow environment is a critical component of understanding basic HSC biology. Previous work by other groups, however, has demonstrated that the mechanisms by which the stem cells migrate to the bone marrow is unclear. Preliminary studies by us suggest that the stem cells may migrate to the bone marrow using previously unrecognized G-protein signaling pathways. Currently our research is focused on the role of this signaling pathway in HSC homing and bone marrow hematopoiesis.
Selected Publications
Adams GB, Scadden DT. - A niche opportunity for stem cell therapeutics. - Gene Ther [ 2008 ] Jan;15(2):96-9 . PubMed
Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, Kronenberg HM, Scadden DT. - Therapeutic targeting of a stem cell niche. - Nat Biotechnol [ 2007 ] Feb;25(2):238-43 . PubMed
Adams GB, Scadden DT. - The hematopoietic stem cell in its place. - Nat Immunol [ 2006 ] Apr;7(4):333-7 . PubMed
Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, Kos CH, Pollak MR, Brown EM, Scadden DT. - Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. - Nature [ 2006 ] Feb 2;439(7076):599-603 . PubMed
Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y, Tschudy KS, Tilly JC, Cortes ML, Forkert R, Spitzer T, Iacomini J, Scadden DT, Tilly JL. - Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. - Cell [ 2005 ] Jul 29;122(2):303-15 . PubMed
Craiu A, Saito Y, Limon A, Eppich HM, Olson DP, Rodrigues N, Adams GB, Dombkowski D, Richardson P, Schlossman R, Choi PS, Grogins J, O'Connor PG, Cohen K, Attar EC, Freshman J, Rich R, Mangano JA, Gribben JG, Anderson KC, Scadden DT. - Flowing cells through pulsed electric fields efficiently purges stem cell preparations of contaminating myeloma cells while preserving stem cell function. - Blood [ 2005 ] Mar 1;105(5):2235-8 . PubMed
Chabner KT, Adams GB, Qiu J, Moskowitz M, Marsters ES, Topulos GP, Scadden DT. - Direct vascular delivery of primitive hematopoietic cells to bone marrow improves localization but not engraftment. - Blood [ 2004 ] Jun 15;103(12):4685-6 . PubMed
