CD48
CD48 antigen precursor (B-lymphocyte activation marker BLAST-1) (BCM1 surface antigen) (Leukocyte antigen MEM-102) (SLAM family member 2) (SLAMF2) (Signaling lymphocytic activation molecule 2) (TCT.1) [BCM1] [BLAST1]
PublicationsПравить
Supplemental Angiopoietin 1 (Ang1) exerts its therapeutic potential on microvascular regression-associated diseases, and this potential is linked with the function of hematopoietic stem cells (HSCs). However, the underlying mechanisms of the effect of enhanced angiogenesis on the modulation of HSCs are not yet defined. Here, we generated transgenic mice expressing Cartilage Oligomeric Matrix Protein (COMP)-Ang1 in keratin 14-expressing cells. The mutant animals expressed excessive angiogenic characteristics in the skin and bone marrow (BM) along with redder skin with more numerous and branched vessels compared with their wild-type (WT) littermates. The mutants displayed reduced long bone formation and osteoclast activity than did WT littermates and had fewer CD150 CD48 Lineage Sca-1 c-Kit (LSK) cells in the BM. The mutants also exhibited greater senescence-associated (SA) β-gal activity, p16 protein expression, and superoxide anion levels in CD150 CD48 LSK cells in the BM. Furthermore, transplantation assay revealed that the mutant-derived LSK cells were inferior to the cells derived from WT littermate in inducing competitive repopulating capacity in the recipients. Collectively, our results demonstrate that persistent and prolonged administration of COMP-Ang1 by inducible transgenic expression mediates excessive angiogenesis in the body and impairs BM microenvironment, eventually leading to senescence of BM HSCs.
MeSH Terms
- Angiopoietin-1
- Animals
- Bone Marrow
- Cartilage Oligomeric Matrix Protein
- Cellular Microenvironment
- Cellular Senescence
- Gene Expression
- Hematopoietic Stem Cells
- Humans
- Mice, Transgenic
- Mutation
- Neovascularization, Physiologic
- Osteoclasts
- Recombinant Fusion Proteins
Keywords
- Angiogenesis
- Bone marrow
- COMP-Ang1
- Hematopoietic stem cells
- Senescence
Recent advances have increased the purity of hematopoietic stem cells (HSCs) isolated from young mouse bone marrow. However, little attention has been paid to the purity of HSCs from other contexts. Although Thy-1 low Sca-1 Lineage- c-kit cells from young bone marrow are highly enriched for HSCs (1 in 5 cells gives long-term multilineage reconstitution after transplantation into irradiated mice), the same population from old, reconstituted, or cytokine-mobilized mice engrafts much less efficiently (1 in 78 to 1 in 185 cells gives long-term multilineage reconstitution). To test whether we could increase the purity of HSCs isolated from these contexts, we examined the SLAM family markers CD150 and CD48. All detectable HSCs from old, reconstituted, and cyclophosphamide/G-CSF-mobilized mice were CD150 CD48-, just as in normal young bone marrow. Thy-1 low Sca-1 Lineage- c-kit cells from old, reconstituted, or mobilized mice included mainly CD48 and/or CD150- cells that lacked reconstituting ability. CD150 CD48- Sca-1 Lineage- c-kit cells from old, reconstituted, or mobilized mice were much more highly enriched for HSCs, with 1 in 3 to 1 in 7 cells giving long-term multilineage reconstitution. SLAM family receptor expression is conserved among HSCs from diverse contexts, and HSCs from old, reconstituted, and mobilized mice engraft relatively efficiently after transplantation when contaminating cells are eliminated.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Antigens, Ly
- Antineoplastic Agents, Alkylating
- CD48 Antigen
- Cell Separation
- Cyclophosphamide
- Glycoproteins
- Graft Survival
- Granulocyte Colony-Stimulating Factor
- Hematopoietic Stem Cell Mobilization
- Hematopoietic Stem Cell Transplantation
- Hematopoietic Stem Cells
- Immunoglobulins
- Membrane Proteins
- Mice
- Proto-Oncogene Proteins c-kit
- Receptors, Cell Surface
- Signaling Lymphocytic Activation Molecule Family Member 1
- Thy-1 Antigens
- Whole-Body Irradiation