Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.
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) f...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2017-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC5279751?pdf=render |
id |
doaj-c6123e826fd9460c8151dd163fa340b6 |
---|---|
record_format |
Article |
spelling |
doaj-c6123e826fd9460c8151dd163fa340b62020-11-25T02:19:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e016601410.1371/journal.pone.0166014Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.Ying HanLanzhu YueMax WeiXiubao RenZonghong ShaoLing ZhangRoss L LevinePearlie K Epling-BurnetteMyelofibrosis 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.http://europepmc.org/articles/PMC5279751?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ying Han Lanzhu Yue Max Wei Xiubao Ren Zonghong Shao Ling Zhang Ross L Levine Pearlie K Epling-Burnette |
spellingShingle |
Ying Han Lanzhu Yue Max Wei Xiubao Ren Zonghong Shao Ling Zhang Ross L Levine Pearlie K Epling-Burnette Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis. PLoS ONE |
author_facet |
Ying Han Lanzhu Yue Max Wei Xiubao Ren Zonghong Shao Ling Zhang Ross L Levine Pearlie K Epling-Burnette |
author_sort |
Ying Han |
title |
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis. |
title_short |
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis. |
title_full |
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis. |
title_fullStr |
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis. |
title_full_unstemmed |
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis. |
title_sort |
mesenchymal cell reprogramming in experimental mplw515l mouse model of myelofibrosis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2017-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5279751?pdf=render |
work_keys_str_mv |
AT yinghan mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT lanzhuyue mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT maxwei mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT xiubaoren mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT zonghongshao mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT lingzhang mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT rossllevine mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis AT pearliekeplingburnette mesenchymalcellreprogramminginexperimentalmplw515lmousemodelofmyelofibrosis |
_version_ |
1724874246904086528 |