title: Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.
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.
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida, United States of America.|Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida, United States of America.|Department of Hematology, Tianjin medical University General Hospital, Tianjin, PR China.
authors.forename: Lanzhu
authors.initials: L
authors.lastname: Yue
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Max
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Hematology, Tianjin medical University General Hospital, Tianjin, PR China.
authors.forename: Zonghong
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Hematopathology, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Leukemia Center, Memorial Sloan Kettering Cancer Center, New York City, New York, United States of America.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Pearlie K
authors.initials: PK
authors.lastname: Epling-Burnette
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D055728:Primary Myelofibrosis / Q000473:pathology*; D053628:Receptors, Thrombopoietin / Q000235:genetics; D015398:Signal Transduction; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D053628:Receptors, Thrombopoietin; D016212:Transforming Growth Factor beta; D003094:Collagen