Secreted Frizzled-Related Protein 1 Extrinsically Regulates Cycling Activity and Maintenance of Hematopoietic Stem Cells

Jonas Renström; Rouzanna Istvanffy; Kerstin Gauthier; Akihiko Shimono; Jörg Mages; Ana Jardon-Alvarez; Monika Kröger; Matthias Schiemann; Dirk H. Busch; Irene Esposito; Roland Lang; Christian Peschel; Robert A.J. Oostendorp

doi:10.1016/j.stem.2009.05.020

Secreted Frizzled-Related Protein 1 Extrinsically Regulates Cycling Activity and Maintenance of Hematopoietic Stem Cells

Jonas Renström
, Rouzanna Istvanffy
, Kerstin Gauthier
, Akihiko Shimono
, Jörg Mages
, Ana Jardon-Alvarez
, Monika Kröger
, Matthias Schiemann
, Dirk H. Busch
, Irene Esposito
, Roland Lang
, Christian Peschel
, Robert A.J. Oostendorp

Technical University of Munich
National University of Singapore
Helmholtz Zentrum München German Research Center for Environmental Health

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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 β-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 β-catenin.

Original language	English
Pages (from-to)	157-167
Number of pages	11
Journal	Cell Stem Cell
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2009.05.020
State	Published - 7 Aug 2009

Keywords

STEMCELL

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10.1016/j.stem.2009.05.020

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Renström, J., Istvanffy, R., Gauthier, K., Shimono, A., Mages, J., Jardon-Alvarez, A., Kröger, M., Schiemann, M., Busch, D. H., Esposito, I., Lang, R., Peschel, C., & Oostendorp, R. A. J. (2009). Secreted Frizzled-Related Protein 1 Extrinsically Regulates Cycling Activity and Maintenance of Hematopoietic Stem Cells. Cell Stem Cell, 5(2), 157-167. https://doi.org/10.1016/j.stem.2009.05.020

@article{81155ce11c9c42178112802bcf846ee9,

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 β-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 β-catenin.",

keywords = "STEMCELL",

author = "Jonas Renstr{\"o}m and Rouzanna Istvanffy and Kerstin Gauthier and Akihiko Shimono and J{\"o}rg Mages and Ana Jardon-Alvarez and Monika Kr{\"o}ger and Matthias Schiemann and Busch, \{Dirk H.\} and Irene Esposito and Roland Lang and Christian Peschel and Oostendorp, \{Robert A.J.\}",

note = "Funding Information: The authors would like to thank Dr. Ulrich Keller for critical reading of the manuscript, Dr. T. Brill, the animal caretakers of the Centre for Preclinical Research for mouse colony maintenance, S. Schill for help with irradiating the animals used in this procedure, and finally K. G{\"o}tsch for technical assistance. The authors gratefully acknowledge the financial support of the German Research Foundation (DFG, grants SFB456-B2, OO 8/2-1, and -2). ",

year = "2009",

month = aug,

day = "7",

doi = "10.1016/j.stem.2009.05.020",

language = "English",

volume = "5",

pages = "157--167",

journal = "Cell Stem Cell",

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Renström, J, Istvanffy, R, Gauthier, K, Shimono, A, Mages, J, Jardon-Alvarez, A, Kröger, M, Schiemann, M, Busch, DH, Esposito, I, Lang, R, Peschel, C & Oostendorp, RAJ 2009, 'Secreted Frizzled-Related Protein 1 Extrinsically Regulates Cycling Activity and Maintenance of Hematopoietic Stem Cells', Cell Stem Cell, vol. 5, no. 2, pp. 157-167. https://doi.org/10.1016/j.stem.2009.05.020

TY - JOUR

T1 - Secreted Frizzled-Related Protein 1 Extrinsically Regulates Cycling Activity and Maintenance of Hematopoietic Stem Cells

AU - Renström, Jonas

AU - Istvanffy, Rouzanna

AU - Gauthier, Kerstin

AU - Shimono, Akihiko

AU - Mages, Jörg

AU - Jardon-Alvarez, Ana

AU - Kröger, Monika

AU - Schiemann, Matthias

AU - Busch, Dirk H.

AU - Esposito, Irene

AU - Lang, Roland

AU - Peschel, Christian

AU - Oostendorp, Robert A.J.

N1 - Funding Information: The authors would like to thank Dr. Ulrich Keller for critical reading of the manuscript, Dr. T. Brill, the animal caretakers of the Centre for Preclinical Research for mouse colony maintenance, S. Schill for help with irradiating the animals used in this procedure, and finally K. Götsch for technical assistance. The authors gratefully acknowledge the financial support of the German Research Foundation (DFG, grants SFB456-B2, OO 8/2-1, and -2).

PY - 2009/8/7

Y1 - 2009/8/7

N2 - 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 β-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 β-catenin.

AB - 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 β-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 β-catenin.

KW - STEMCELL

UR - https://www.scopus.com/pages/publications/67849122659

U2 - 10.1016/j.stem.2009.05.020

DO - 10.1016/j.stem.2009.05.020

M3 - Article

C2 - 19664990

AN - SCOPUS:67849122659

SN - 1934-5909

VL - 5

SP - 157

EP - 167

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

Secreted Frizzled-Related Protein 1 Extrinsically Regulates Cycling Activity and Maintenance of Hematopoietic Stem Cells

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