CD45 in stem cell microenvironment

The hematopoietic stem cell (HSC) microenvironment is a complex environment, which supports the survival of static hematopoietic stem cells and the expansion, differentiation, and migration of precursor cells during hematopoietic cell replenishment. 1,2 The stromal cells supporting the most primitive hematopoietic stem cells in the endosteal microenvironment are actually a mixture of fibroblasts, reticulocytes expressing CXCL12 / SDF-1, endothelial cells and bone-forming osteoblasts. 1,2 Recently, studies have shown that bone resorption osteoclasts also play a role in the microenvironment. 3 Current evidence indicates that this effect involves hematopoietic transmembrane tyrosine phosphatase CD45. 4. CD45 exists on the surface of all hematopoietic cells, including hematopoietic stem cells and osteoclasts, which are of hematopoietic origin. 4,5 Among its substrates, Src family kinase (SFK) is one of the most thoroughly studied CD45 substrates. CD45 can positively or negatively affect the activity of SFK, depending on which phosphate tyrosine phosphate group it removed. 5 CD45 deletion mutations in humans are associated with severe immunodeficiency. This is mainly due to the absence of CD45 on T cells, which should normally be present in large amounts. CD45 on T cells is necessary for the regulation of SFK activity in the antigen response. 5 CD45-deficient (CD45-/-) mouse bone marrow contains normal numbers of hematopoietic cells, but the most primitive hematopoietic stem cells are reduced in number, and their response to G-CSF mobilization is also impaired. 4 To some extent, this defect is an inherent feature of this hematopoietic stem cell; without the down-regulation of CD45-mediated SFK activity, integrin-mediated adhesion increases correspondingly, while hematopoietic stem cells tend to stay at In the microenvironment. CD45-/-deficient hematopoietic stem cells do not respond to G-CSF stimulation mobilization and chemokine CXCL12 / SDF-1 induced homing, which negatively affects cell implantation after transplantation. 4 These defects can be rebuilt and repaired by supplementing with SFK inhibitors, meaning that this effect is usually performed by CD45. 4 Similarly, CD45-deficient (CD45-/-) receptors also exhibit implantation defects and subsequent mobilization defects of normal hematopoietic stem cells, showing the role of CD45 in the microenvironment and hematopoietic stem cells. 4

Although G-CSF is widely used to induce stem cell mobilization into the peripheral circulation, many other "pressure signals" also have a mobilization effect. 6 TRANCE (TNF-related activation-inducing factor), also known as RANK L (receptor activator of NF-kB ligand) is one such mobilizer. 3,4 However, in CD45-/-mice, RANK L can no longer mobilize hematopoietic stem cells. Since osteoclasts are the main cell type expressing RANK L receptors in the microenvironment, this shows that osteoclast CD45 is involved in RANK L-induced mobilization. 4 RANK L is better known as a regulator necessary for osteoclast differentiation, and this function is also impaired in CD45-/-mice. In addition to abnormal morphology and microenvironment remodeling, CD45-/-osteoclasts showed impaired secretion of metalloproteinases stimulated by G-CSF, and decreased osteopontin degradation stimulated by RANK L, and soluble stem cell factor (SCF; c -kit ligand) release. 4 These events are known to be regulated by SFK and are important for hematopoietic stem cell mobilization. 3,7-9

Although the role of CD45 in dephosphorylation of SFK and other substrates has been confirmed in a variety of leukocytes, the role of CD45 in osteoclasts is a new discovery. 5 There are still some questions about CD45, which have not yet been answered, including its inherent reason for its highly adjustable expression of its isotype and other differentiated glycosylation forms, and the identification of its potential extracellular ligands. However, the involvement of osteoclasts CD45 in the osseous endometrium microenvironment system and hematopoietic stem cell mobilization provides researchers with new clues that the role of osteoclasts, whether directly or indirectly, has a dynamic balance on hematopoietic stem cells Very important.

The downstream process of CD45 is involved in the mobilization of hematopoietic stem cells
CD45 dephosphorylates and down-regulates the activity of Src family kinase (SFK) in hematopoietic stem cells. This simultaneously reduces integrin activity and adhesion, such as between hematopoietic stem cells α4β1 and reticular cells VCAM-1. CD45 also down-regulates the SFK activity of osteoclasts, allowing TRANCE / RANK L to induce the secretion of MMP-9 and other proteases. These proteases catalyze the release of soluble stem cell factor (SCF) from osteoblasts and the degradation of CXCL12 / SDF-1. These usually interact with hematopoietic stem cells SCF R / c-kit and CXCR4, respectively. The loss of these interactions leads to the mobilization of hematopoietic stem cells from bone marrow to blood.

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