Format

Send to

Choose Destination
Stem Cells. 2016 Jan;34(1):67-82. doi: 10.1002/stem.2229. Epub 2015 Oct 23.

P-Selectin Sustains Extramedullary Hematopoiesis in the Gata1 low Model of Myelofibrosis.

Author information

1
Department of Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, Utah, USA.
2
CEA/DSV/iRCM/LRTS, Inserm U967, Fontenay-aux-Roses Cedex, Paris, France.
3
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità
4
Department of Medicine, Campus Biomedico, Rome, Italy.
5
Istituto Genetica Medica, Centro Nazionale Ricerche, and Medicine and Aging Sciences, Section of Human Momorphology, University G. D'Annunzio, Chieti, Italy.
6
Department of Biomedical Sciences, Alma Mater University, Bologna, Italy.
7
Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.

Abstract

Splenomegaly is a major manifestation of primary myelofibrosis (PMF) contributing to clinical symptoms and hematologic abnormalities. The spleen from PMF patients contains increased numbers of hematopoietic stem cells (HSC) and megakaryocytes (MK). These MK express high levels of P-selectin (P-sel) that, by triggering neutrophil emperipolesis, may cause TGF-β release and disease progression. This hypothesis was tested by deleting the P-sel gene in the myelofibrosis mouse model carrying the hypomorphic Gata1(low) mutation that induces megakaryocyte abnormalities that recapitulate those observed in PMF. P-sel(null) Gata1(low) mice survived splenectomy and lived 3 months longer than P-sel(WT) Gata1(low) littermates and expressed limited fibrosis and osteosclerosis in the marrow or splenomegaly. Furthermore, deletion of P-sel disrupted megakaryocyte/neutrophil interactions in spleen, reduced TGF-β content, and corrected the HSC distribution that in Gata1(low) mice, as in PMF patients, is abnormally expanded in spleen. Conversely, pharmacological inhibition of TGF-β reduced P-sel expression in MK and corrected HSC distribution. Spleens, but not marrow, of Gata1(low) mice contained numerous cKIT(pos) activated fibrocytes, probably of dendritic cell origin, whose membrane protrusions interacted with MK establishing niches hosting immature cKIT(pos) hematopoietic cells. These activated fibrocytes were not detected in spleens from P-sel(null) Gata1(low) or TGF-β-inhibited Gata1(low) littermates and were observed in spleen, but not in marrow, from PMF patients. Therefore, in Gata1(low) mice, and possibly in PMF, abnormal P-sel expression in MK may mediate the pathological cell interactions that increase TGF-β content in MK and favor establishment of a microenvironment that supports myelofibrosis-related HSC in spleen.

KEYWORDS:

Activated fibrocytes; Extramedullary hematopoiesis; Megakaryocytes; Myelofibrosis-related stem cells; P-selectin; TGF-β

PMID:
26439305
DOI:
10.1002/stem.2229
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center