Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice.
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.
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
Yi
Y
Liu
Department of Toxicology and Cancer Biology, University of Kentucky, Health Sciences Research Building Room 340, 1095 V.A. Drive, Lexington, KY 40536, USA.
Cuiping
C
Zhang
Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
Zhenyu
Z
Li
Department of Cancer Biostatistics, University of Kentucky, Lexington, KY 40536, USA.
Chi
C
Wang
Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Jianhang
J
Jia
Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Tianyan
T
Gao
Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
Gerhard
G
Hildebrandt
Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Daohong
D
Zhou
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
Subbarao
S
Bondada
Department of Pathology, Northwestern University, Chicago, IL 60611, USA.
Peng
P
Ji
Department of Toxicology and Cancer Biology, University of Kentucky, Health Sciences Research Building Room 340, 1095 V.A. Drive, Lexington, KY 40536, USA.
Daret
D
St Clair
Department of Computer Science, University of Kentucky, Lexington, KY 40536, USA.
Jinze
J
Liu
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA.
Changguo
C
Zhan
Cincinnati Children's Hospital Medical Center, Experimental Hematology and Cancer Biology, Cincinnati, OH 45229, USA; Institute for Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
Hartmut
H
Geiger
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA.
Shuxia
S
Wang
Department of Toxicology and Cancer Biology, University of Kentucky, Health Sciences Research Building Room 340, 1095 V.A. Drive, Lexington, KY 40536, USA. Electronic address: ying.liang@uky.edu.
Ying
Y
Liang
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D017353:Gene Deletion; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*
D009419:Nerve Tissue Proteins; C000618833:latexin protein, mouse
expansion; hematopoietic stem cell; latexin; repopulating advantage; survival; thrombospondin 1