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

© 2017 The Author(s).

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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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 ).

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

Supplemental Information includes five figures and can be found with this article online at http://dx.doi.org/10.1016/j.stemcr.2017.02.009

PIIS2213671117300760_mmc1.pdf (293 kB)
Document S1. Figures S1–S5