Niche-dependent model for human myelodysplasia

The study of human myelodysplastic syndromes (MDS) has been challenging because patient-derived hematopoietic cells cannot be efficiently expanded in a model system. We have now developed a strategy to grow patient-diseased stem cells (the cells that maintain the disease) in mice, by co-injecting a subset of non-hematopoietic cells, isolated from the same patient’s bone marrow. This model provides a proof of concept that the microenvironment, referred to as “the niche”, is critical to support the diseased stem cells in human MDS and opens new avenues for therapeutic targeting for this disease.

HFSP Long-Term Fellow Hind Medyouf and colleagues
authored on Wed, 23 April 2014

Myelodysplastic syndromes are a group of heterogeneous diseases mainly affecting the elderly (45/100,000 in >70 years old), characterized by the inability to generate mature blood cells from bone marrow stem cells with an increased propensity to developing acute myeloid leukemia, a type of aggressive blood cancer that is difficult to treat. Because of the inefficient production of mature blood cells, MDS patients suffer from a poor quality of life due to chronic anemia, excessive bleeding, and and/or recurrent infections. Most MDS patients rely on continuous blood or platelet transfusions, a treatment that isassociated with secondary side effects (e.g. excess iron) and complications. To date, no curative treatment exists for MDS, except for hematopoietic stem cell transplantation, which is unfortunately not an option for nearly 90% of the patients (too old and/or no suitable donor).

A number of bottlenecks have hampered our ability to develop new drugs to treat MDS.  First, isolating the MDS “stem cell”, which maintains the disease, has been difficult due to the complex mixture of cells in the bone marrow of MDS patients. Second, we lack good methods to grow the cells outside the body. To tackle these challenges, we developed a strategy to grow human MDS in mice, by co-transplanting MDS hematopoietic cells together with mesenchymal stromal cells (a non-hematopoietic subtype of niche cells) isolated from the same patient into immunocompromised mice. Importantly, niche cells obtained from healthy donors, were significantly less efficient in promoting MDS propagation in mice. We compared healthy versus MDS niche cells and uncovered a number of changes in key niche factors. Importantly, some of these changes could be experimentally induced in healthy niche cells simply by exposing them to diseased hematopoietic cells from MDS patients, using an in vitro co-culture system. As such, this work reveals the existence of a critical bi-directional cross talk between MDS cells and their niche counterpart in human MDS and highlights the importance of the microenvironment in human myelodysplasia.

Figure: Schematic view of the xenograft model developed in this study. Bone marrow-derived niche cells (Mesenchymal stromal cells=MSC) and MDS hematopoietic stem cells (lin-CD34+CD38-) are isolated from bone marrow biopsies of MDS patients and simultaneously co-injected in the bone marrow cavity of sub-lethally irradiated immunocompromised mice (NSG or NSGS strains). Up to 28 weeks post transplantation, recipient mice display significant human cell chimersim (human CD45+ cells) with readily detectable dysplastic cells in the bone marrow, one of the main clinical features of MDS. Tracking of patient-specific mutations using pyrosequencing, confirmed that most of the xenografted human cells carry the molecular lesion (SF3B1 mutation K700E) that was identified in the original patient, thus demonstrating that the model allows for the expansion of MDS derived cells as opposed to the normal residual hematopoietic stem cells present in the patient biopsy.

The newly established model allows a functional screening of factors that are essential for disease propagation. By disrupting the effects of the deregulated candidate factors, we hope to prevent MDS growth and provide new means for therapeutic treatment of this disease. Being able to generate patient-specific models could be a first step in this direction.


Myelodysplastic cells in patients re-program mesenchymal stromal cells to establish a transplantable stem cell-niche disease unit. Hind Medyouf, Maximilian Mossner, Johann-Christoph Jann, Florian Nolte, Simon Raffel, Carl Herrmann, Amelie Lier, Christian Eisen, Verena Nowak, Bettina Zens, Katja Müdder, Corinna Klein, Julia Obländer, Stephanie Fey, Jovita Vogler, Alice Fabarius, Eva Riedl, Henning Roehl, Alexander Kohlmann, Marita Staller, Claudia Haferlach, Nadine Müller, Thilo John, Uwe Platzbecker, Georgia Metzgeroth, Wolf-Karsten Hofmann, Andreas Trumpp and Daniel Nowak. Cell Stem Cell 2014, DOI: 10.1016/j.stem.2014.02.014.

Pubmed link

Link to abstract