title: The effects of Gremlin1 on human umbilical cord blood hematopoietic progenitors.
abstract: Bone morphogenetic proteins (BMPs) support malignant hematopoiesis in CML. Conversely, the multi-functional BMP antagonist Gremlin1 supports self-renewing cancer stem cells of other malignancies. Inhibition of BMP signaling in CML, or of Gremlin1 in solid tumors, may therefore have therapeutic potential. However, since BMPs regulate hematopoietic stem cell (HSC) decisions in the stem cell niche, it is necessary to determine how Gremlin1 influences normal HSC. We examined the effects of Gremlin1 on long-term culture-initiating cells (LTC-IC) and transplantable hematopoietic stem cells (SCID-repopulating cells: SRC) in human umbilical cord blood. Gremlin1 inhibited BMP signaling, downregulated BMP-6 and cyclin E2 expression and upregulated hairy and enhancer of split-1 (HES-1; a Notch transcriptional target) and Hedgehog interacting protein-1 (HHIP-1; an inhibitor of Hedgehog signaling). The functional effects of Gremlin1 on SRC, i.e. skewing of their myelopoietic:lymphopoietic potential towards B lymphopoiesis without affecting long-term engraftment potential, were entirely consistent with changes in gene expression induced by Gremlin1. Since both BMPs and Gremlin1 are secreted by osteoblasts in vivo, our studies provide potential insights into the molecular regulation of hematopoiesis in the stem cell niche. These results also suggest that Gremlin1 (and possibly its mimetics that may be developed for therapeutic use) may not adversely affect normal human hematopoietic stem cell survival, though they may reduce their myelopoietic potential.
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA; Hematology/Oncology/Transplantation Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Shekels
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Colvin Wanshura
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Nelson
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Stephenson
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA.
authors.forename: Shaukat A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: Hematology/Oncology Section, Minneapolis VA Health Care System, Minneapolis, MN, USA; Hematology/Oncology/Transplantation Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. Electronic address: pankaj.gupta@va.gov.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D055418:Bone Morphogenetic Protein 6 / Q000096:biosynthesis; D002352:Carrier Proteins / Q000096:biosynthesis; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D016213:Cyclins / Q000096:biosynthesis; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D038041:Lymphopoiesis / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D038042:Myelopoiesis / Q000187:drug effects*; D055153:Stem Cell Niche / Q000187:drug effects*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D055418:Bone Morphogenetic Protein 6; D002352:Carrier Proteins; D016213:Cyclins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D000072056:Transcription Factor HES-1; C525816:BMP6 protein, human; C503688:CCNE2 protein, human; C486399:GREM1 protein, human; C117596:HHIP protein, human; C078493:HES1 protein, human
keywords: Bone morphogenetic proteins; Gremlin 1 protein, human; Hematopoietic stem cell transplantation; Hematopoietic stem cells; Mice, SCID; Transcription factors