title: Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A-null mice.
abstract: Despite its wide use as a marker for hematopoietic stem cells (HSCs), the function of stem cell antigen-1 (Sca-1) (also known as lymphocyte activation protein-6A [Ly-6A]) in hematopoiesis remains poorly defined. We have previously established that Sca-1(-/-) T cells develop normally, although they are hyperresponsive to antigen. Here, we report detailed analysis of hematopoiesis in Sca-1-deficient animals. The differentiation potential of Sca-1-null bone marrow was determined from examination of the most mature precursors (culture colony-forming units [CFU-Cs]) to less committed progenitors (spleen CFUs [CFU-Ss]) to long-term repopulating HSCs. Sca-1-null mice are mildly thrombocytopenic with a concomitant decrease in megakaryocytes and their precursors. Bone marrow cells derived from Sca-1(-/-) mice also have decreased multipotential granulocyte, erythroid, macrophage, and megakaryocyte CFU (GEMM-CFU) and CFU-S progenitor activity. Competitive repopulation assays demonstrated that Sca-1(-/-) HSCs are at a competitive disadvantage compared with wild-type HSCs. To further analyze the potential of Sca-1(-/-) HSCs, serial transplantations were performed. While secondary repopulations using wild-type bone marrow completely repopulated Sca-1(-/-) mice, Sca-1(-/-) bone marrow failed to rescue one third of lethally irradiated wild-type mice receiving secondary bone marrow transplants from irradiation-induced anemia and contributed poorly to the surviving transplant recipients. These data strongly suggest that Sca-1 is required for regulating HSC self-renewal and the development of committed progenitor cells, megakaryocytes, and platelets. Thus, our studies conclusively demonstrate that Sca-1, in addition to being a marker of HSCs, regulates the developmental program of HSCs and specific progenitor populations.
authors.affiliation: Programme in Cancer/Blood, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Caryn Y
authors.initials: CY
authors.lastname: Ito
authors.forename: Carol Y J
authors.initials: CY
authors.lastname: Li
authors.forename: Alan
authors.initials: A
authors.lastname: Bernstein
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000502:physiology*; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000166:cytology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins