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

Authors

Yi Liu, University of Kentucky
Cuiping Zhang, University of KentuckyFollow
Zhenyu Li, University of KentuckyFollow
Chi Wang, University of KentuckyFollow
Jianhang Jia, University of KentuckyFollow
Tianyan Gao, University of KentuckyFollow
Gerhard C. Hildebrandt, University of KentuckyFollow
Daohong Zhou, University of Arkansas at Little Rock
Subbarao Bondada, University of KentuckyFollow
Peng Ji, Northwestern University
Daret K. St. Clair, University of KentuckyFollow
Jinze Liu, University of KentuckyFollow
Chang-Guo Zhan, University of KentuckyFollow
Hartmut Geiger, Cincinnati Children's Hospital
Shuxia Wang, University of KentuckyFollow
Ying Liang, University of KentuckyFollow

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.

Document Type

Article

Publication Date

3-16-2017

Notes/Citation Information

Published in Stem Cell Reports, v. 8, issue 4, p. 991-1004.

© 2017 The Author(s).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.stemcr.2017.02.009

Funding Information

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 ).

Related Content

The accession number for all microarray data reported in this paper is GEO: GSE94665.

Repository Citation

Liu, Yi; Zhang, Cuiping; Li, Zhenyu; Wang, Chi; Jia, Jianhang; Gao, Tianyan; Hildebrandt, Gerhard C.; Zhou, Daohong; Bondada, Subbarao; Ji, Peng; St. Clair, Daret K.; Liu, Jinze; Zhan, Chang-Guo; Geiger, Hartmut; Wang, Shuxia; and Liang, Ying, "Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice" (2017). Toxicology and Cancer Biology Faculty Publications. 67.
https://uknowledge.uky.edu/toxicology_facpub/67