Identification of the haematopoietic stem cell niche and control of the niche size

Jiwang Zhang; Chao Niu; Ling Ye; Haiyang Huang; Xi He; Wei Gang Tong; Jason Ross; Jeff Haug; Teri Johnson; Jian Q. Feng; Stephen Harris; Leanne M. Wiedemann; Yuji Mishina; Linheng Li

doi:10.1038/nature02041

Identification of the haematopoietic stem cell niche and control of the niche size

Jiwang Zhang, Chao Niu, Ling Ye, Haiyang Huang, Xi He, Wei Gang Tong, Jason Ross, Jeff Haug, Teri Johnson, Jian Q. Feng, Stephen Harris, Leanne M. Wiedemann, Yuji Mishina, Linheng Li

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

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Abstract

Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche' - the in vivo regulatory microenvironment where HSCs reside - and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin⁺ CD45 ^- osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and β-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.

Original language	English (US)
Pages (from-to)	836-841
Number of pages	6
Journal	Nature
Volume	425
Issue number	6960
DOIs	https://doi.org/10.1038/nature02041
State	Published - Oct 23 2003
Externally published	Yes

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@article{0248c46721f5484d9d9f72986199154e,

title = "Identification of the haematopoietic stem cell niche and control of the niche size",

abstract = "Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche' - the in vivo regulatory microenvironment where HSCs reside - and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+ CD45 - osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and β-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.",

author = "Jiwang Zhang and Chao Niu and Ling Ye and Haiyang Huang and Xi He and Tong, {Wei Gang} and Jason Ross and Jeff Haug and Teri Johnson and Feng, {Jian Q.} and Stephen Harris and Wiedemann, {Leanne M.} and Yuji Mishina and Linheng Li",

note = "Funding Information: Acknowledgements We thank P. Dijke for providing anti-BMPR1A anti-serum, and C. G. Lobe for Z/EG reporter mice. We thank R. Krumlauf and X. Liao for scientific discussion. We thank H. Lin for critically reviewing the manuscript, and L. Bonewald for training in bone histomorphometry. We are grateful to D. di Natale and T. Langner for assistance in manuscript editing. We are grateful to S. Morris and D. Stark for imaging assistance, W. Walker and her coworkers for animal care, and C. Sonnenbrot and his co-workers for assistance in medium preparation. This work was supported by the Stowers Institute for Medical Research. Funding Information: Acknowledgements We thank C. Charlier and H. Ronne for discussions, M. Laita, B. McTeir, J. Pettersson, A.-C. Svensson and M. K{\"o}ping-H{\"o}gg{\aa}rd for technical assistance, and the Pig Improvement Company for providing DNA samples from Berkshire and Gloucester Old Spot pigs. This work was supported by the Belgian Minist{\`e}re des Classes Moyennes et de l{\textquoteright}Agriculture, the AgriFunGen program at the Swedish University of Agricultural Sciences, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, Gentec, the UK Department for Environment, Food and Rural Affairs, the UK Pig Breeders Consortium, and the Biotechnology and Biological Sciences Research Council.",

year = "2003",

month = oct,

day = "23",

doi = "10.1038/nature02041",

language = "English (US)",

volume = "425",

pages = "836--841",

journal = "Nature",

issn = "0028-0836",

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T1 - Identification of the haematopoietic stem cell niche and control of the niche size

AU - Zhang, Jiwang

AU - Niu, Chao

AU - Ye, Ling

AU - Huang, Haiyang

AU - He, Xi

AU - Tong, Wei Gang

AU - Ross, Jason

AU - Haug, Jeff

AU - Johnson, Teri

AU - Feng, Jian Q.

AU - Harris, Stephen

AU - Wiedemann, Leanne M.

AU - Mishina, Yuji

AU - Li, Linheng

N1 - Funding Information: Acknowledgements We thank P. Dijke for providing anti-BMPR1A anti-serum, and C. G. Lobe for Z/EG reporter mice. We thank R. Krumlauf and X. Liao for scientific discussion. We thank H. Lin for critically reviewing the manuscript, and L. Bonewald for training in bone histomorphometry. We are grateful to D. di Natale and T. Langner for assistance in manuscript editing. We are grateful to S. Morris and D. Stark for imaging assistance, W. Walker and her coworkers for animal care, and C. Sonnenbrot and his co-workers for assistance in medium preparation. This work was supported by the Stowers Institute for Medical Research. Funding Information: Acknowledgements We thank C. Charlier and H. Ronne for discussions, M. Laita, B. McTeir, J. Pettersson, A.-C. Svensson and M. Köping-Höggård for technical assistance, and the Pig Improvement Company for providing DNA samples from Berkshire and Gloucester Old Spot pigs. This work was supported by the Belgian Ministère des Classes Moyennes et de l’Agriculture, the AgriFunGen program at the Swedish University of Agricultural Sciences, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, Gentec, the UK Department for Environment, Food and Rural Affairs, the UK Pig Breeders Consortium, and the Biotechnology and Biological Sciences Research Council.

PY - 2003/10/23

Y1 - 2003/10/23

N2 - Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche' - the in vivo regulatory microenvironment where HSCs reside - and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+ CD45 - osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and β-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.

AB - Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche' - the in vivo regulatory microenvironment where HSCs reside - and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+ CD45 - osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and β-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.

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Identification of the haematopoietic stem cell niche and control of the niche size

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