Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit.
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.
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.
Hind
H
Medyouf
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Maximilian
M
Mossner
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Johann-Christoph
JC
Jann
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Florian
F
Nolte
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, German.
Simon
S
Raffel
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany.
Carl
C
Herrmann
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, German.
Amelie
A
Lier
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, German.
Christian
C
Eisen
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Verena
V
Nowak
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.
Bettina
B
Zens
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.
Katja
K
Müdder
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.
Corinna
C
Klein
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Julia
J
Obländer
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Stephanie
S
Fey
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Jovita
J
Vogler
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Alice
A
Fabarius
Department of Pathology, University Hospital Mannheim, 68167 Mannheim, Germany.
Eva
E
Riedl
Department of Orthopedics, University Hospital Mannheim, 68167 Mannheim, Germany.
Henning
H
Roehl
Munich Leukemia Laboratory (MLL), 81377 Munich, Germany.
Alexander
A
Kohlmann
Munich Leukemia Laboratory (MLL), 81377 Munich, Germany.
Marita
M
Staller
Munich Leukemia Laboratory (MLL), 81377 Munich, Germany.
Claudia
C
Haferlach
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Nadine
N
Müller
Department of Traumatology, DRK Hospital Westend, 14050 Berlin, Germany.
Thilo
T
John
Technical University Dresden, University Hospital 'Carl Gustav Carus,' Medical Clinic and Policlinic I, 01307 Dresden, Germany.
Uwe
U
Platzbecker
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Georgia
G
Metzgeroth
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Wolf-Karsten
WK
Hofmann
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.
Andreas
A
Trumpp
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
Daniel
D
Nowak
D000368:Aged; D000818:Animals; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology*; D055153:Stem Cell Niche