Smad4 in osteoblasts exerts a differential impact on HSC fate depending on osteoblast maturation stage.
Osteoblasts (OBs) are indispensable for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow microenvironment. Here we investigated how Smad4 modulates HSC fate at distinct stages of OB development. For this, we conditionally knocked out Smad4 in cells expressing type I collagen (Col1a1) and osteocalcin (OC), respectively. Col1a1-expressing OBs were widely present in both the trabecular and cortical compartment, whereas OC-expressing OBs were predominantly located in the cortical compartment. HSCs from Col1a1 mutants displayed senescence-associated phenotypes. OC mutants did not exhibit HSC senescence-related phenotypes, but instead showed preferential HSC death. Of note, stromal cell-derived factor 1 expression was lower in Col1a1 mutants than control littermates, suggesting potential impairment of CXCR4-CXCL12-mediated HSC retention. Disruption of the CXCR4-CXCL12 axis by AMD3100 administration led to an increase in the senescence-associated β-galactosidase activity and low competitive potential. Collectively, our findings indicate that deletion of Smad4 in OBs differentially modulates HSC fate in a stage-dependent manner.
Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju, South Korea.|Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea.
S-H
SH
Kook
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea.
C-Y
CY
Yun
Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju, South Korea.
H-J
HJ
Sim
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea.
G
G
Bhattarai
University of Pittsburgh Cancer Institute, Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
B-C
BC
Lee
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea.
K-Y
KY
Lee
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea.
E-S
ES
Cho
Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju, South Korea.|Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience and School of Dentistry, Chonbuk National University School of Dentistry, Jeonju, South Korea.
J-C
JC
Lee
D000818:Animals; D001853:Bone Marrow; D000071556:Cancellous Bone / Q000166:cytology; D002454:Cell Differentiation; D019070:Cell Lineage; D016922:Cellular Senescence; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D000071538:Cortical Bone / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000737:chemistry / Q000166:cytology*; D015675:Osteocalcin / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000502:physiology*
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015675:Osteocalcin