TY - JOUR
T1 - Gli1+ Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target
AU - Schneider, Rebekka K.
AU - Mullally, Ann
AU - Dugourd, Aurelien
AU - Peisker, Fabian
AU - Hoogenboezem, Remco
AU - Van Strien, Paulina M.H.
AU - Bindels, Eric M.
AU - Heckl, Dirk
AU - Büsche, Guntram
AU - Fleck, David
AU - Müller-Newen, Gerhard
AU - Wongboonsin, Janewit
AU - Ventura Ferreira, Monica
AU - Puelles, Victor G.
AU - Saez-Rodriguez, Julio
AU - Ebert, Benjamin L.
AU - Humphreys, Benjamin D.
AU - Kramann, Rafael
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1+ mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1+ cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1+ cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy. Schneider and colleagues show that Gli1+ bone marrow mesenchymal stromal cells are an important source of fibrotic cells during bone marrow fibrosis and that targeting of Gli proteins with GANT61 holds promise for amelioration of this disease.
AB - Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1+ mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1+ cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1+ cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy. Schneider and colleagues show that Gli1+ bone marrow mesenchymal stromal cells are an important source of fibrotic cells during bone marrow fibrosis and that targeting of Gli proteins with GANT61 holds promise for amelioration of this disease.
KW - bone marrow fibrosis
KW - Gli1
KW - mesenchymal stem cells
KW - myelofibrosis
KW - myeloproliferative neoplasms
UR - http://www.scopus.com/inward/record.url?scp=85018173491&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2017.03.008
DO - 10.1016/j.stem.2017.03.008
M3 - Article
C2 - 28457748
AN - SCOPUS:85018173491
VL - 20
SP - 785
EP - 800
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 6
ER -