Evidence for organ-specific stem cell microenvironments.
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-beta, VEGF, osteocalcin, PDGF-alpha, 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.
Ghinassi
Barbara
B
Department of Medicine, Tish Cancer Institute, Mount Sinai School of Medicine, The Myeloproliferative Disease Consortium, New York, New York 10029, USA.
Martelli
Fabrizio
F
Verrucci
Maria
M
D'Amore
Emanuela
E
Migliaccio
Giovanni
G
Vannucchi
Alessandro Maria
AM
Hoffman
Ronald
R
Migliaccio
Anna Rita
AR
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D049109:Cell Proliferation; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D004777:Environment; D005110:Extracellular Space / Q000502:physiology; D005260:Female; D006411:Hematopoiesis, Extramedullary / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D013156:Splenectomy; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins