title: Secreted frizzled-related protein 1 extrinsically regulates cycling activity and maintenance of hematopoietic stem cells.
abstract: Secreted frizzled-related protein 1 (Sfrp1) is highly expressed by stromal cells maintaining hematopoietic stem cells (HSCs). Sfrp1 loss in stromal cells increases production of hematopoietic progenitors, and in knockout mice, dysregulates hemostasis and increases Flk2- Cd34- Lin- Sca1+ Kit+ (LSK) cell numbers in bone marrow. Also, LSK and multipotent progenitors (MPPs) resided mainly in the G0/G1 phase of cell cycle, with an accompanying decrease in intracellular beta-catenin levels. Gene-expression studies showed a concomitant decrease Ccnd1 and Dkk1 in Cd34- LSK cells and increased expression of Pparg, Hes1, and Runx1 in MPP. Transplantation experiments showed no intrinsic effect of Sfrp1 loss on the number of HSCs or their ability to engraft irradiated recipients. In contrast, serial transplantations of wild-type HSCs into Sfrp1(-/-) mice show a progressive decrease of wild-type LSK and MPP numbers. Our results demonstrate that Sfrp1 is required to maintain HSC homeostasis through extrinsic regulation of beta-catenin.
authors: 3rd Department of Internal Medicine, Klinikum rechts der Isar, Munich, Germany.
authors: Jonas
authors: J
authors: Renström
authors: Rouzanna
authors: R
authors: Istvanffy
authors: Kerstin
authors: K
authors: Gauthier
authors: Akihiko
authors: A
authors: Shimono
authors: Jörg
authors: J
authors: Mages
authors: Ana
authors: A
authors: Jardon-Alvarez
authors: Monika
authors: M
authors: Kröger
authors: Matthias
authors: M
authors: Schiemann
authors: Dirk H
authors: DH
authors: Busch
authors: Irene
authors: I
authors: Esposito
authors: Roland
authors: R
authors: Lang
authors: Christian
authors: C
authors: Peschel
authors: Robert A J
authors: RA
authors: Oostendorp
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D051176:beta Catenin / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D019938:Cyclin D1; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047495:PPAR gamma; D011506:Proteins; D000072056:Transcription Factor HES-1; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C530105:Ccnd1 protein, mouse; C501127:Dkk1 protein, mouse; C489734:Hes1 protein, mouse; C493726:Runx1 protein, mouse