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Cell Stem Cell. 2014 Jun 5;14(6):824-37. doi: 10.1016/j.stem.2014.02.014. Epub 2014 Apr 3.

Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit.

Author information

1
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; German Cancer Consortium, 69120 Heidelberg, Germany. Electronic address: hind.medyouf@uniklinikum-dresden.de.
2
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
3
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, German.
4
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany.
5
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, German.
6
Department of Pathology, University Hospital Mannheim, 68167 Mannheim, Germany.
7
Department of Orthopedics, University Hospital Mannheim, 68167 Mannheim, Germany.
8
Munich Leukemia Laboratory (MLL), 81377 Munich, Germany.
9
Department of Traumatology, DRK Hospital Westend, 14050 Berlin, Germany.
10
Technical University Dresden, University Hospital 'Carl Gustav Carus,' Medical Clinic and Policlinic I, 01307 Dresden, Germany.
11
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, German; German Cancer Consortium, 69120 Heidelberg, Germany. Electronic address: a.trumpp@dkfz-heidelberg.de.

Abstract

Myelodysplastic syndromes (MDSs) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem and progenitor cells (HSPCs) and possibly the HSPC niche. Here, we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating Lin(-)CD34(+)CD38(-) stem cells in orthotopic xenografts. Overproduction of niche factors such as CDH2 (N-Cadherin), IGFBP2, VEGFA, and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets in order to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt MDS MSC-like molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of the microenvironment. Therefore, this patient-derived xenograft model provides functional and molecular evidence that MDS is a complex disease that involves both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.

PMID:
24704494
DOI:
10.1016/j.stem.2014.02.014
[Indexed for MEDLINE]
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