Secreted frizzled-related protein 1 extrinsically regulates cycling activity and maintenance of hematopoietic stem cells.
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.
Renström
Jonas
J
3rd Department of Internal Medicine, Klinikum rechts der Isar, Munich, Germany.
Istvanffy
Rouzanna
R
Gauthier
Kerstin
K
Shimono
Akihiko
A
Mages
Jörg
J
Jardon-Alvarez
Ana
A
Kröger
Monika
M
Schiemann
Matthias
M
Busch
Dirk H
DH
Esposito
Irene
I
Lang
Roland
R
Peschel
Christian
C
Oostendorp
Robert A J
RA
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
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