Identification of Chemoattractive Factors Involved in the Migration of Bone Marrow-Derived Mesenchymal Stem Cells to Brain Lesions Caused by Prions

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to brain lesions of neurodegenerative diseases; however, the precise mechanisms by which MSCs migrate remain to be elucidated. In this study, we carried out an in vitro migration assay to investigate the chemoattractive factors for MSCs in the brains of prion-infected mice. The migration of immortalized human MSCs (hMSCs) was reduced by their pretreatment with antibodies against the chemokine receptors, CCR3, CCR5, CXCR3, and CXCR4 and by pretreatment of brain extracts of prion-infected mice with antibodies against the corresponding ligands, suggesting the involvement of these receptors, and their ligands in the migration of hMSCs. In agreement with the results of an in vitro migration assay, hMSCs in the corpus callosum, which are considered to be migrating from the transplanted area toward brain lesions of prion-infected mice, expressed CCR3, CCR5, CXCR3, and CXCR4. The combined in vitro and in vivo analyses suggest that CCR3, CCR5, CXCR3, and CXCR4, and their corresponding ligands are involved in the migration of hMSCs to the brain lesions caused by prion propagation. In addition, hMSCs that had migrated to the right hippocampus of prion-infected mice expressed CCR1, CX3CR1, and CXCR4, implying the involvement of these chemokine receptors in hMSC functions after chemotactic migration. Further elucidation of the mechanisms that underlie the migration of MSCs may provide useful information regarding application of MSCs to the treatment of prion diseases.

Hypoxic Culture Conditions as a Solution for Mesenchymal Stem Cell Based Regenerative Therapy

“…Furthermore, expression of chemokine receptors CXCR4, CXCR7, and CX3CR1 was upregulated when MSCs were exposed to hypoxia or a reagent that mimics the response to hypoxia [94, 113–115]. These chemokine receptors play an important role in damaged-tissue-specific trafficking and homing of MSCs [113, 115–118]. …”

Effect of a CCR1 receptor antagonist on systemic trafficking of MSCs and polyethylene particle-associated bone loss

“…Subsequently, locally and systemically recruited activated macrophages differentiate into multinucleated giant cells and osteoclasts leading to bone resorption around implants within a foreign body reaction [16]. Among the large number of chemokine receptors, CCR1 (C-C motif receptor 1) plays a major role in the recruitment of mesenchymal stem cells (MSCs) [17–19]. Huang et al [20] have shown the ability of CCR1 to increase MSC chemotaxis, viability and engraftment using a murine model of injured myocardium.…”

Matrix metalloproteinase‐1‐mediated mesenchymal stem cell tumor tropism is dependent on crosstalk with stromal derived growth factor 1/C‐X‐C chemokine receptor 4 axis

“…Furthermore, blocking CXCR‐4 alone does not affect MSC migration unless the enforced expression of CXCR‐4 was employed in the setting of myocardial infarct heart (13, 14), and in tumors (15). Other studies have employed preconditioning of MSCs with a cocktail of cytokines to induce the up‐regulation of CXCR‐4 for MSC migration (16, 17), suggesting that other factors could crosstalk with these GPCRs.…”