Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

Yi Liu; Cuiping Zhang; Zhenyu Li; Chi Wang; Jianhang Jia; Tianyan Gao; Gerhard Hildebrandt; Daohong Zhou; Subbarao Bondada; Peng Ji; Daret St. Clair; Jinze Liu; Changguo Zhan; Hartmut Geiger; Shuxia Wang; Ying Liang

doi:10.1016/j.stemcr.2017.02.009

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

Yi Liu, Cuiping Zhang, Zhenyu Li, Chi Wang, Jianhang Jia, Tianyan Gao, Gerhard Hildebrandt, Daohong Zhou, Subbarao Bondada, Peng Ji, Daret St. Clair, Jinze Liu, Changguo Zhan, Hartmut Geiger, Shuxia Wang, Ying Liang

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

20 Scopus citations

Abstract

Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit.

Original language	English
Pages (from-to)	991-1004
Number of pages	14
Journal	Stem Cell Reports
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.stemcr.2017.02.009
State	Published - Apr 11 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)

Funding

Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the NIH under Award Number RO1HL124015 (Y. Liang), the Edward P. Evans Foundation (S.B., D.S.C., D.Z., H.G., and Y. Liang), and the Biostatistics and Bioinformatics Shared Resource(s), Flow Cytometry Core of the University of Kentucky Markey Cancer Center (P30CA177558). We thank Carol Swiderski, Yanan You, and Rong Wen for technical assistance, and Garretson Epperly in the Imaging Core of the University of Kentucky Markey Cancer Center for confocal microscope imaging assistance, and the Markey Cancer Center's Research Communications Office for editing and graphics support.

Funders	Funder number
The Markey Biostatistics and Bioinformatics Shared Resource Facility
Markey Cancer Center
National Institutes of Health (NIH)	RO1HL124015
National Heart, Lung, and Blood Institute (NHLBI)
National Childhood Cancer Registry – National Cancer Institute	P30CA060553
Edward P Evans Foundation
University of Kentucky Markey Cancer Center	P30CA177558

Keywords

expansion
hematopoietic stem cell
latexin
repopulating advantage
survival
thrombospondin 1

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2017.02.009

Cite this

Liu, Y., Zhang, C., Li, Z., Wang, C., Jia, J., Gao, T., Hildebrandt, G., Zhou, D., Bondada, S., Ji, P., St. Clair, D., Liu, J., Zhan, C., Geiger, H., Wang, S., & Liang, Y. (2017). Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice. Stem Cell Reports, 8(4), 991-1004. https://doi.org/10.1016/j.stemcr.2017.02.009

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abstract = "Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit.",

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Liu, Y, Zhang, C, Li, Z, Wang, C , Jia, J , Gao, T, Hildebrandt, G, Zhou, D, Bondada, S, Ji, P, St. Clair, D, Liu, J, Zhan, C, Geiger, H, Wang, S & Liang, Y 2017, 'Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice', Stem Cell Reports, vol. 8, no. 4, pp. 991-1004. https://doi.org/10.1016/j.stemcr.2017.02.009

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T1 - Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

AU - Liu, Yi

AU - Zhang, Cuiping

AU - Li, Zhenyu

AU - Wang, Chi

AU - Jia, Jianhang

AU - Gao, Tianyan

AU - Hildebrandt, Gerhard

AU - Zhou, Daohong

AU - Bondada, Subbarao

AU - Ji, Peng

AU - St. Clair, Daret

AU - Liu, Jinze

AU - Zhan, Changguo

AU - Geiger, Hartmut

AU - Wang, Shuxia

AU - Liang, Ying

PY - 2017/4/11

Y1 - 2017/4/11

N2 - Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit.

AB - Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit.

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