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Leptin-receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis

Abstract

Bone marrow fibrosis is a critical component of primary myelofibrosis (PMF). However, the origin of the myofibroblasts that drive fibrosis is unknown. Using genetic fate mapping we found that bone marrow leptin receptor (Lepr)-expressing mesenchymal stromal lineage cells expanded extensively and were the fibrogenic cells in PMF. These stromal cells downregulated the expression of key haematopoietic-stem-cell-supporting factors and upregulated genes associated with fibrosis and osteogenesis, indicating fibrogenic conversion. Administration of imatinib or conditional deletion of platelet-derived growth factor receptor a (Pdgfra) from Lepr+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Conversely, activation of the PDGFRA pathway in bone marrow Lepr+ cells led to expansion of these cells and extramedullary haematopoiesis, features of PMF. Our data identify Lepr+ stromal lineage cells as the origin of myofibroblasts in PMF and suggest that targeting PDGFRA signalling could be an effective way to treat bone marrow fibrosis.

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Figure 1: TOE mice develop clinical features of PMF.
Figure 2: HSCs overproliferate and mobilize to the spleen in TOE mice.
Figure 3: Bone marrow mesenchymal stromal cells undergo expansion and fibrotic conversion in PMF.
Figure 4: Bone marrow mesenchymal stromal cells downregulate key HSC maintenance factors, CXCL12 and SCF.
Figure 5: Mesenchymal stromal cells upregulate fibrosis and osteogenesis genes in PMF.
Figure 6: Deletion of Pdgfra from mesenchymal stromal cells or administrating imatinib ameliorates bone marrow fibrosis.
Figure 7: Activation of the PDGFRA pathway in Lepr+ cells leads to mesenchymal stromal cell expansion and HSC mobilization.

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Acknowledgements

This work was supported by the MPN Research Foundation. L.D. and J.L. were supported by the Rita Allen Foundation and the National Heart, Lung and Blood Institute (1R01HL132074). Flow cytometry was partly supported by the NIH (S10RR027050 and S10OD020056). We thank R. Schwabe at Columbia and D. Brenner at UC San Diego for providing Col-gfp mice. We thank L. Olson at Oklahoma Medical Research Foundation and P. Soriano at Icahn School of Medicine at Mount Sinai for providing PdgfraD842V mice. We thank S. Weyn-Vanhentenryck, C. Zhang and R. Schwabe at Columbia for help in analysing gene expression data. We thank S. Ho and A. Figueroa for help with flow cytometry.

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Authors

Contributions

G.W., M.D., L.M.-M., Y.L. and L.D. carried out all experiments with the help of Q.L. and J.L. M.D., L.M.-M., G.W. and L.D. designed the experiments, interpreted the results and wrote the manuscript.

Corresponding author

Correspondence to Lei Ding.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 2 HSCs progressively mobilize to the spleen as PMF advances. (Related to Fig. 2).

(a) Bone marrow multipotent progenitors (n = 17 mice for control, n = 5 mice for intermediate TOE, n = 10 mice for advanced TOE) and LSK hematopoietic progenitors (n = 12 mice for control, n = 4 mice for intermediate TOE, n = 6 mice for advanced TOE) increased in intermediate then decreased in advanced stage of PMF. (b) Representative flow cytometry plots for quantifying BrdU incorporation in HSCs after a 5-day BrdU pulse. (c) Spleen HSC frequency gradually increased from intermediate to advanced PMF mice (n = 22 mice for control, n = 15 mice for intermediate TOE, n = 10 mice for advanced TOE). (d) Spleen cellularity gradually increased from intermediate to advanced PMF mice (n = 15 mice for control, n = 6 mice for intermediate TOE, n = 7 mice for advanced TOE). (e,f) Spleen HSC number (n = 13 mice for control, n = 6 mice for intermediate TOE, n = 7 mice for advanced TOE), MPP number (n = 9 mice for control, n = 4 mice for intermediate TOE, n = 7 mice for advanced TOE) and HPC (LSK) number (n = 5 mice for control, n = 3 mice for intermediate TOE, n = 3 mice for advanced TOE) gradually increased from intermediate to advanced PMF mice. (g) An increased total HSC number (bone marrow plus spleen) in intermediate PMF mice was followed by a reduction in advanced PMF mice (n = 12 mice for control, n = 6 mice for intermediate TOE, n = 7 mice for advanced TOE). Data represent mean ± s.e.m. Two-tailed student’s t-tests were used to assess statistical significance: P < 0.05, P < 0.001.

Supplementary Figure 3 Bone marrow mesenchymal stromal lineage cells expand and assume a fibrotic cell fate. (Related to Fig. 3).

(a) Bone marrow CD45/Ter119-CD140a+ mesenchymal stromal cell frequency increased as PMF developed from intermediate to advanced stages (n = 17 mice for control, n = 12 mice for intermediate TOE, n = 8 mice for advanced TOE). (b) Bone marrow mesenchymal stromal lineage cells expanded 6.5 fold as quantified by counting TdTomato + cells on bone marrow sections from vector control and TOE mice (n = 4 images for control and TOE each, data represent mean ± s.e.m. Two-tailed student’s t-tests were used to assess statistical significance: P < 0.001). (c,d) Lepr-cre-expressing mesenchymal stromal cells expanded extensively and displayed elongated fibroblast-like stromal cell morphology. Arrow heads point to elongated fibroblast-like cells. (e) In Lepr-cre; loxptdTomato; Col-gfp control or TOE mice, all tdTomato+ cells are GFP+. (f) In Lepr-cre; loxptdTomato; Col-gfp control or TOE mice, nearly all GFP+ cells are tdTomato+. Images are representative of at least 3 biological replicates.

Supplementary Figure 4 Bone marrow mesenchymal stromal cells down-regulate CXCL12 and SCF, and display a fibrotic cell morphology. (Related to Fig. 4).

(a,b) Representative images showing normal Cxcl12-DsRed expression in Cxcl12DsRed/+ mice transplanted with control virus-infected bone marrow cells. (c,d) Images showing Cxcl12-DsRed expression in TOE mice. Arrow heads point to elongated fibroblast-like stromal cells. (e) qPCR analysis showing downregulation of Scf and Cxcl12 in bone marrow mesenchymal stromal cells from intermediate stage to advanced stage PMF mice (n = 4 mice for control, n = 4 mice for intermediate PMF and n = 4 mice for advanced PMF). Data represent mean ± s.d. Two-tailed student’s t-tests were used to assess statistical significance. (f) Representative flow cytometry plots showing CD45/Ter119Scf-GFP+ stromal cells. Images are representative of at least 3 biological replicates.

Supplementary Figure 5 Gene expression profiling analysis of mesenchymal stromal cells from PMF mice. (Related to Fig. 5).

(a) Representative flow cytometric plots showing the gates to sort CD45/Ter119/CD31Cxcl12-DsRed+ stromal cells from PMF and control bone marrow. A total of three freshly double-sorted aliquots of cells ( 5,000) from PMF (from 5 mice) and control (from 3 mice) Cxcl12DsRed/+ mice were used for gene expression analysis. (b) Normalized expression levels of mesenchymal cell markers and HSC niche factors by CD45/Ter119/CD31Cxcl12-DsRed+ stromal cells from PMF and control bone marrow. Values represent mean ± s.d. from three biological replicates. (c) List of fibrosis genes used to performed GSEA in Fig. 5c. (d) List of osteogenic genes used to performed GSEA in Fig. 5d.

Supplementary Figure 6 Lepr-cre; Pdgfrafl/− mice have normal HSC function and Lepr-cre; Pdgfrafl/fl TOE mice fail to develop bone marrow fibrosis (Related to Fig. 6).

(a) Flow cytometry plots showing efficient deletion of PDGFRa. (b) A competitive reconstitution assay for Lepr-cre; Pdgfrafl/− and control mice. 5 × 105 donor bone marrow cells from Lepr-cre; Pdgfrafl/− adult mice or control Lepr-cre; Pdgfrafl+ mice were competitively transplanted with 5 × 105 recipient bone marrow cells into irradiated recipient mice. The percentages of donor-derived Mac-1+ myeloid, CD3+ T, and B220+ B cells in the blood were analyzed for 16 weeks after transplantation (n = 5 recipient mice for each genotype). Data represent mean ± s.d. Two-tailed student’s t-tests were used to assess statistical significance. (c) Lepr-cre; Pdgfrafl/fl TOE mice displayed enlarged spleens and imatinib-treated TOE mice showed normal sized spleens. (d) Representative reticulin staining on spleen sections from Lepr-cre; Pdgfrafl/fl TOE mice revealed excessive deposition of reticulin fibers, similar to control TOE mice. (e) Confocal images showing similar levels of megakaryocyte hyperplasia in the bone marrow from Lepr-cre; Pdgfrafl/fl and control TOE mice. CD41 is a marker for megakaryocytes (red). Nuclei were stained with DAPI (blue). (f) Bone marrow sections from Lepr-cre; Pdgfrafl/fl and control TOE mice were subjected to reticulin staining. While control TOE mice robustly developed bone marrow fibrosis, none of the Lepr-cre; Pdgfrafl/fl TOE mice had bone marrow fibrosis. (g) Representative flow cytometry plots showing effective suppression of bone marrow stromal cell expansion in Lepr-cre; Pdgfrafl/fl TOE and imatinib-treated TOE mice. (h) Spleen sections from control and TOE + imatinib were subjected to reticulin staining. Images are representative of at least 3 biological replicates.

Supplementary Figure 7 Lepr-cre; PdgfraD842V/+ mice have bone marrow stromal fibrotic conversion and HSC mobilization (Related to Fig. 7).

(a) Flow cytometry analysis revealed normal bone marrow stromal cell frequency from Lepr-cre; PdgfraD842V/+ mice (n = 3 mice for control, n = 4 mice for D842V KI). (b) Representative reticulin staining on bone marrow sections from Lepr-cre; PdgfraD842V/+ and control mice. (c) Normal bone marrow cellularity (n = 4 mice for control, n = 5 mice for D842V KI) and HPC frequency of Lepr-cre; PdgfraD842V/+ mice (n = 5 mice for control, n = 6 mice for D842V KI). (d) HSC frequency in livers from Lepr-cre; PdgfraD842V/+ mice (n = 5 mice for control, n = 6 mice for D842V KI). Data represent mean ± s.d. Two-tailed student’s t-tests were used to assess statistical significance. Images are representative of at least 3 biological replicates.

Supplementary Table 1 A list of genes that were significantly up-regulated in mesenchymal stromal cells from PMF mice compared with controls. P values were determined by ANOVA test via an online NIA Array Analysis software (www.lgsun.grc.nia.nih.gov/ANOVA). TOE, Tpo-overexpressing. Con, control vector virus.

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Decker, M., Martinez-Morentin, L., Wang, G. et al. Leptin-receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis. Nat Cell Biol 19, 677–688 (2017). https://doi.org/10.1038/ncb3530

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