title: Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap.
abstract: Red cell production is primarily determined by the action of erythropoietin. Additional erythropoiesis-regulatory factors include molecules and cellular interactions occurring within the bone marrow (BM) microenvironment. Sotatercept (ACE-011) is an activin receptor ligand trap that binds several members of the TGF-β superfamily. Treatment with ACE-011 reverses bone loss and reduces the degree of osteoporosis, but it is accompanied by elevated hemoglobin and hematocrit levels. The mechanisms underlying the beneficial effects of ACE-011 on red cell production remain unknown. This study explores the means by which ACE-011 promotes erythropoiesis. We showed that ACE-011 does not directly affect erythroid differentiation of human CD34(+) cells in vitro. We next tested whether ACE-011 acts indirectly by affecting BM accessory cells. Conditioned media produced by BM stromal cells (SCs) inhibited erythroid differentiation of CD34(+) cells while maintained their ability to proliferate. However, conditioned media from SCs treated with ACE-011 partially restored erythropoiesis, coinciding with changes in the molecular and secretory profile of SCs, including the expression and secretion of erythropoiesis-modulatory factors. We conclude that inhibitory factors produced by BM SCs in vitro might control erythropoiesis in vivo and that agents that reverse these microenvironmental signals could provide an approach to attenuate anemia in clinical conditions.
authors.affiliation: Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA. camelia.iancu-rubin@mssm.edu
authors.forename: Camelia
authors.initials: C
authors.lastname: Iancu-Rubin
authors.forename: Goar
authors.initials: G
authors.lastname: Mosoyan
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraus
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D000328:Adult; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects* / Q000502:physiology; D005312:Fetal Blood / Q000166:cytology; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins; D017154:Stromal Cells / Q000187:drug effects* / Q000502:physiology
chemical_list: D030301:Activin Receptors, Type II; D017077:Culture Media, Conditioned; D016207:Cytokines; D008024:Ligands; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C542017:sotatercept