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Site-1 protease ablation in the osterix-lineage in mice results in bone marrow neutrophilia and hematopoietic stem cell alterations
- Source :
- Biology Open, article-version (VoR) Version of Record, Biology Open, Vol 9, Iss 6 (2020)
- Publication Year :
- 2020
- Publisher :
- The Company of Biologists, 2020.
-
Abstract
- Site-1 protease (S1P) ablation in the osterix-lineage in mice drastically reduces bone development and downregulates bone marrow-derived skeletal stem cells. Here we show that these mice also suffer from spina bifida occulta with a characteristic lack of bone fusion in the posterior neural arches. Molecular analysis of bone marrow-derived non-red blood cell cells, via single-cell RNA-Seq and protein mass spectrometry, demonstrate that these mice have a much-altered bone marrow with a significant increase in neutrophils and Ly6C-expressing leukocytes. The molecular composition of bone marrow neutrophils is also different as they express more and additional members of the stefin A (Stfa) family of proteins. In vitro, recombinant Stfa1 and Stfa2 proteins have the ability to drastically inhibit osteogenic differentiation of bone marrow stromal cells, with no effect on adipogenic differentiation. FACS analysis of hematopoietic stem cells show that despite a decrease in hematopoietic stem cells, S1P ablation results in an increased production of granulocyte-macrophage progenitors, the precursors to neutrophils. These observations indicate that S1P has a role in the lineage specification of hematopoietic stem cells and/or their progenitors for development of a normal hematopoietic niche. Our study designates a fundamental requirement of S1P for maintaining a balanced regenerative capacity of the bone marrow niche.<br />Summary: Ablation of S1P in the osterix-lineage downregulates bone development due to hematopoietic progenitor alterations that increase bone marrow neutrophils with accompanying increases in stefin proteins with osteogenic inhibitory activity.
- Subjects :
- Stromal cell
QH301-705.5
Neutrophils
Science
Biology
Neutrophilia
Osterix
General Biochemistry, Genetics and Molecular Biology
Immunophenotyping
Blood cell
Mice
Osteogenesis
medicine
Animals
Cell Lineage
Biology (General)
Stefin
Progenitor cell
Genetic Association Studies
Mice, Knockout
Osteopenia
Gene Expression Profiling
Serine Endopeptidases
Hematopoietic stem cell
Cell Differentiation
Hematopoietic Stem Cells
Spine
Hematopoiesis
Cell biology
Haematopoiesis
medicine.anatomical_structure
Sp7 Transcription Factor
Site-1 protease
Proprotein Convertases
Bone marrow
Single-Cell Analysis
medicine.symptom
Stem cell
General Agricultural and Biological Sciences
Research Article
Subjects
Details
- ISSN :
- 20466390
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Biology Open
- Accession number :
- edsair.doi.dedup.....4172c4354fdd2ce5c0e824190984826b