The role of mesenchymal stromal cells for the hematopoietic insufficiency in myelodysplastic syndromes

• Applicant: Dr. Thomas Schroeder
• Subject Area: Hematology, Oncology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278045970

Myelodyplastic syndromes (MDS) are a heterogenous group of clonal bone marrow disorders characterized by a variable hematopoietic insufficiency. Accordingly, MDS patients suffer from anemia symptoms, bleeding and infections, with hematopoeitic insufficiency representing the major cause for morbidity and mortality. As MDS are considered disorders of hematopoietic stem and progenitor cells (HSPC), research was mainly focused on HSPC during the last years.Mesenchymal stromal cells (MSC) are an integral component of the bone marrow microenvironment, in which HSPC reside and sustain a life-long balance between self-renewal and differentiation. During the last decade it could be demonstrated, that physiologically MSC are in spatial and functional contact with HSPC thereby essentially involved in the regulation of hematopoiesis.Recent work from our group as well as other research groups has clearly shown that MSC from MDS patients are structurally and functionally altered in comparison to healthy controls. As a consequence hematopoietic support function of MDS-derived MSC is substantially diminished. These data demonstrate that MSC are definitely involved in the development of hematopoietic insufficiency in MDS. However, they do not allow any conclusions so far, whether these MSC defects are primary, or whether they represent secondary alterations as a reaction to the expanding MDS-HSPC clone.Based on clinical observations and our own preliminary data we favor the latter hypothesis, that the invading MDS clone functionally inhibits MSC. To address this hypothesis we will perform a three-step experimental program: In a 1st step we aim to demonstrate that clonal MDS-HSPC functionally inhibit MSC. Therefore, we will simulate the in vivo situation of BM infiltration by coculturing of MDS-HSPC with healthy MSC. Subsequently, functionality of these experimentally manipulated MSC will be tested in order to see whether these alterations are comparable to those of ex-vivo investigated MDS-MSC. Complementary, we will also use the NUP98/HOXD13 mouse model, which allows to sequentially investigate the effects of the expanding MDS clone on primary healthy MSC. To identify potential myelosuppressive candidate mechanisms, we will perform in the 2nd step gene expression profiling of manipulated human MSC as well as MSC obtained from the NUP98/HOXD13 model. This procedure should effectively allow a reciprocal identification and subsequent verification of inhibitory effector mechanisms in MDS-HSPC. In the 3rd step we will perform gain and loss of function experiments aiming to evaluate the biological relevance of these identified mechanisms. Idealistically, this would allow to revert stroma dysfunction and restore hematopoietic support function of MSC thereby representing a direct therapeutic approach to treat hematopoietic insufficiency and related symptoms in MDS.

• DFG Programme: Research Grants
• Cooperation Partner: Professor Dr. Frank Lyko