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Updated: Mar 8, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis
Ying Han1,2, Lanzhu Yue1,3, Max Wei1
1Department of Immunology, Moffitt Cancer Center, Tampa, Florida, United States of America.
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.
Insights
Mesenchymal stromal cells (MSCs) drive myelofibrosis in myeloproliferative neoplasms (MPNs) by overproducing collagen. Fibroblast Growth Factor beta (FGFb) shows promise in reversing this fibrosis by targeting key signaling pathways.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- Myelofibrosis, characterized by bone marrow (BM) fibrosis, indicates a poor prognosis in myeloproliferative neoplasms (MPNs).
- The exact mechanisms driving extracellular matrix remodeling and collagen deposition in the MPN BM niche are not fully understood.
Purpose of the Study:
- To investigate the role of mesenchymal stromal cells (MSCs) in myelofibrosis pathogenesis within MPNs.
- To explore potential therapeutic targets for reversing fibrosis in MPNs.
Main Methods:
- Isolated MSCs from mice with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow.
- Assessed collagen deposition in MSCs in vitro and in vivo.
- Investigated the role of TGFβ, pSmad3, pSTAT3, and FGFb signaling pathways.
Main Results:
- MSCs from MPLW515L recipients showed excessive collagen deposition, indicating in vivo reprogramming.
- TGFβ was equally expressed by MSCs from both MPLWT and MPLW515L mice, and anti-TGFβ antibodies only partially reduced collagen secretion.
- Profibrotic MSCs exhibited increased pSmad3 and pSTAT3 levels, suggesting inflammatory mediators cooperate with TGFβ signaling.
- FGFb treatment reduced collagen deposition in MSCs from MPLW515L mice, highlighting the vulnerability of the activating pathway.
Conclusions:
- MSCs play a critical role in MPN-associated myelofibrosis, independent of viral presence or neoplastic hematopoietic cells.
- TGFβ signaling alone is insufficient to fully explain collagen deposition, with inflammatory mediators like pSmad3 and pSTAT3 being crucial.
- FGFb represents a potential therapeutic strategy to reverse fibrosis in MPNs by targeting specific signaling pathways.
