Abstract
Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
| Original language | English |
|---|---|
| Pages (from-to) | 637-652.e8 |
| Journal | Cell Stem Cell |
| Volume | 28 |
| Issue number | 4 |
| Early online date | 9 Dec 2020 |
| DOIs | |
| Publication status | Published - 1 Apr 2021 |
Bibliographical note
Funding Information:R.K. was supported by grants from the Deutsche Forschungsgemeinschaft German Research Foundation (DFG; SCHN1188/5-1, SFBTRR219, and SFBTRR57), a grant from the European Research Council (ERC-StG 677448), and a grant from the Interdisciplinary Centre for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University (O3-11). R.K.S. is an Oncode Institute investigator and was supported by grants from the MPN Foundation (2017 MPNRF/LLS Award), a KWF Kankerbestrijding young investigator grant (11031/2017?1, Bas Mulder Award; Dutch Cancer Foundation), and an ERC grant (deFIBER; ERC-StG 757339). This work was in part supported by grants of the Deutsche Forschungsgemeinschaft (DFG) (German Research Foundation) to R.K. (KR 4073/9-1), R.K.S. (SCHN1188/6-1), T.B. (BR1782/5-1), S.K. (KO2155/7-1), and I.C. (GE2811/4-1) within the clinical research unit CRU344. R.K. I.G.C. and R.K.S. are members of the E:MED Consortia Fibromap funded by the German Ministry of Education and Science (BMBF). P.B. was financially supported by DFG (SFB/TRR57, SFB/TRR219, BO3755/6-1), BMBF (STOP-FSGS-01GM1901A), and the IZKF (O3-2). N.B.L. was supported DFG (BA 6349/1-1). H.F.E.G. was supported by the European Union's Horizon 2020 research and innovation program under a Marie Curie-Sklodowska grant (707404 LEaDing Fellow). I.G.C. was supported by an IZKF grant (E8-15). We thank the team of the Translational Research Unit of the Institute of Pathology of the University of Bern as well as the team of the Institute for Clinical Chemistry, Molecular Diagnostics and Pathology (PARTS) at Erasmus Medical Center, Rotterdam. We further would like to thank Remco Hoogenboezem for excellent support in processing raw sequencing data for downstream analysis. N.B.L. and H.F.E.G. designed and carried out experiments, analyzed results, and wrote the manuscript. L.R. performed the biocomputational analysis, interpreted the results, and wrote the manuscript. I.A.M.S. J.S.N. S.F. C.K. U.S.A.S. B.B. and E.B. performed experiments, analyzed, interpreted data, and reviewed the manuscript. G.B. H.K. I.G. P.K. T.V. K.H.L. Y.B. P.B. E.W.-Y.T. T.H.B. S.K. and M.C. selected patient specimens, performed stainings on murine and human tissues, and reviewed the manuscript. R.K. I.G.C. and R.K.S. obtained funding, designed the study, performed experiments, analyzed data, and wrote the manuscript. All authors provided critical analysis of the manuscript. The authors declare no competing interests.
Funding Information:
R.K. was supported by grants from the Deutsche Forschungsgemeinschaft German Research Foundation (DFG; SCHN1188/5-1 , SFBTRR219 , and SFBTRR57 ), a grant from the European Research Council ( ERC-StG 677448 ), and a grant from the Interdisciplinary Centre for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University ( O3-11 ). R.K.S. is an Oncode Institute investigator and was supported by grants from the MPN Foundation ( 2017 MPNRF/LLS Award ), a KWF Kankerbestrijding young investigator grant ( 11031/2017–1 , Bas Mulder Award; Dutch Cancer Foundation ), and an ERC grant (deFIBER; ERC-StG 757339 ). This work was in part supported by grants of the Deutsche Forschungsgemeinschaft ( DFG ) (German Research Foundation) to R.K. ( KR 4073/9-1 ), R.K.S. ( SCHN1188/6-1 ), T.B. ( BR1782/5-1 ), S.K. ( KO2155/7-1 ), and I.C. ( GE2811/4-1 ) within the clinical research unit CRU344 . R.K., I.G.C., and R.K.S. are members of the E:MED Consortia Fibromap funded by the German Ministry of Education and Science (BMBF). P.B. was financially supported by DFG ( SFB/TRR57 , SFB/TRR219 , BO3755/6-1 ), BMBF ( STOP-FSGS-01GM1901A ), and the IZKF ( O3-2 ). N.B.L. was supported DFG ( BA 6349/1-1 ). H.F.E.G. was supported by the European Union’s Horizon 2020 research and innovation program under a Marie Curie-Sklodowska grant ( 707404 LEaDing Fellow ). I.G.C. was supported by an IZKF grant ( E8-15 ). We thank the team of the Translational Research Unit of the Institute of Pathology of the University of Bern as well as the team of the Institute for Clinical Chemistry, Molecular Diagnostics and Pathology (PARTS) at Erasmus Medical Center, Rotterdam. We further would like to thank Remco Hoogenboezem for excellent support in processing raw sequencing data for downstream analysis.
Publisher Copyright:
© 2020 The Author(s)