Mesenchymal cell reprogramming in experimental MPLW515L mouse model of myelofibrosis

Ying Han, Lanzhu Yue, Max Wei, Xiubao Ren, Zonghong Shao, Ling Zhang, Ross L. Levine, Pearlie K. Epling-Burnette

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    Abstract

    Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFβ production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFβ was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti- TGFβ antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFβ-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFβ signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs.

    Original languageEnglish (US)
    Article numbere0166014
    JournalPloS one
    Volume12
    Issue number1
    DOIs
    StatePublished - Jan 2017

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    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)
    • General

    Cite this

    Han, Y., Yue, L., Wei, M., Ren, X., Shao, Z., Zhang, L., Levine, R. L., & Epling-Burnette, P. K. (2017). Mesenchymal cell reprogramming in experimental MPLW515L mouse model of myelofibrosis. PloS one, 12(1), [e0166014]. https://doi.org/10.1371/journal.pone.0166014