title: Overexpression of Jagged-1 and its intracellular domain in human mesenchymal stromal cells differentially affect the interaction with hematopoietic stem and progenitor cells.
abstract: Mesenchymal stromal cells (MSC) are an important component of the bone marrow microenvironment. Notch ligands expressed by MSC are known to play a regulatory role for hematopoietic stem and progenitor cells (HSPC) and in support of bone marrow homeostasis. While the role of Notch signaling in HSPC, their progeny, and MSC has been relatively well studied, little is known about the Notch-independent regulatory impact of Notch ligands on MSC themselves. In the present study, we used genetically engineered bone marrow-derived human MSC to study the function role of Jagged-1 and the Jagged-1 intracellular domain (JICD) with regard to the interaction with HSPC. We demonstrate that Jagged-1 in human MSC undergoes cleavage to produce an intracellular domain that translocates into the nucleus. JICD but not Jagged-1 overexpression was associated with an increased expression of stromal cell-derived factor-1. Short-term co-culture (7 days) of HSPC with JICD-overexpressing MSC, but not with Jagged-1-overexpressing MSC, led to increased proliferation of CD34(+) progenitors. In contrast, long-term co-culture of HSPC with Jagged-1-overexpressing MSC (up to 6 weeks) led to a significantly better support of cobblestone area-forming cells and long-term culture-initiating cells (LTC-ICs) compared with JICD-overexpressing MSC. Taken together, results of this study indicate that full-length Jagged-1 and JICD have differential effects on MSC and on their interaction with HSPC ex-vivo. JICD-overexpressing MSC induce proliferation of HSPCs in short-term culture at the expense of immature precursors (LTC-ICs), whereas Jagged-1 overexpressing MSC favor LTC-IC formation.
authors.affiliation: 1 Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus , Dresden, Germany .
authors.forename: Regina
authors.initials: R
authors.lastname: Duryagina
authors.forename: Sebastian
authors.initials: S
authors.lastname: Thieme
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anastassiadis
authors.forename: Carsten
authors.initials: C
authors.lastname: Werner
authors.forename: Susan
authors.initials: S
authors.lastname: Schneider
authors.forename: Manja
authors.initials: M
authors.lastname: Wobus
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brenner
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002450:Cell Communication; D002467:Cell Nucleus; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D018952:Antigens, CD34; D002135:Calcium-Binding Proteins; D054377:Chemokine CXCL12; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins