Evidence for organ-specific stem cell microenvironments

doi:10.1002/jcp.22055

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Wiley InterScience

Journal of Cellular Physiology

Volume 223 Issue 2, Pages 460 - 470

Published Online: 28 Jan 2010

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Original Article

Evidence for organ-specific stem cell microenvironments

Barbara Ghinassi^{1 2}, Fabrizio Martelli³, Maria Verrucci³, Emanuela D'Amore⁴, Giovanni Migliaccio⁵, Alessandro Maria Vannucchi⁶, Ronald Hoffman¹, Anna Rita Migliaccio^{1 3 *}

¹Department of Medicine, Tish Cancer Institute, Mount Sinai School of Medicine, The Myeloproliferative Disease Consortium, New York, New York
²Department of Biomorphology, University G. D'Annunzio, Chieti, Italy
³Department of Hematology/Oncology and Molecular Medicine, Instituto Superiore Sanità, Rome, Italy
⁴Department of Quality and Security of Animal Experimentation, Instituto Superiore Sanità, Rome, Italy
⁵Department of Cell Biology and Neurosciences, Instituto Superiore Sanità, Rome, Italy
⁶Department of Hematology, Azienda Ospedaliera Careggi, Florence, Italy

email: Anna Rita Migliaccio (annarita.migliaccio@mssm.edu)

^*Correspondence to Anna Rita Migliaccio, Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, Box #1079, New York, NY 10029.

Funded by:
Ministero per la Ricerca Scientifica and Alleanza sul Cancro, Italy
National Cancer Institute; Grant Number: P01-CA108671

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-

, VEGF, osteocalcin, PDGF-

, 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.

Received: 11 November 2009; Accepted: 7 December 2009

Digital Object Identifier (DOI)

10.1002/jcp.22055 About DOI