Abstract
The X‐linked Gata1^low^ mutation in mice induces strain‐restricted myeloproliferative disorders characterized by extramedullary hematopoiesis in spleen (CD1 and DBA/2) and liver (CD1 only). To assess the role of the microenvironment in establishing this myeloproliferative trait, progenitor cell compartments of spleen and marrow from wild‐type and Gata1^low^ mice were compared. Phenotype and clonal assay of non‐fractionated cells indicated that Gata1^low^ mice contain progenitor cell numbers 4‐fold lower and 10‐fold higher than normal in marrow and spleen, respectively. However, progenitor cells prospectively isolated from spleen, but not from marrow, of Gata1^low^ mice expressed colony‐forming function in vitro. Therefore, calculation of cloning activity of purified cells demonstrated that the total number of Gata1^low^ progenitor cells was 10‐ to 100‐fold lower than normal in marrow and >1,000 times higher than normal in spleen. This observation indicates that Gata1^low^ hematopoiesis is favored by the spleen and is in agreement with our previous report that removal of this organ induces wild‐type hematopoiesis in heterozygous Gata1^low/+^ females (Migliaccio et al., 2009, Blood 114:2107). To clarify if rescue of wild‐type hematopoiesis by splenectomy prevented extramedullary hematopoiesis in liver, marrow cytokine expression profile and liver histopathology of splenectomized Gata1^low/+^ females were investigated. After splenectomy, the marrow expression levels of TGF‐β, VEGF, osteocalcin, PDGF‐α, and SDF‐1 remained abnormally high while Gata1^low^ hematopoiesis was detectable in liver of both CD1 and DBA/2 mutants. Therefore, in the absence of the spleen, Gata1^low^ hematopoiesis is supported by the liver suggesting that treatment of myelofibrosis in these animals requires the rescue of both stem cell and microenvironmental functions. J. Cell. Physiol. 223: 460–470, 2010. © 2010 Wiley‐Liss, Inc.