Mesenchymal stromal cells regulate the cell mobility and the immune response during osteogenesis through secretion of vascular endothelial growth factor A

Abstract

Cell-cell interaction is believed to play a critical role in the cell-based therapy for bone regeneration. However, the mechanisms involved in the interaction between donor cells and host cells during the bone healing process are still not clear. This study investigated the potential effect of vascular endothelial growth factor A (VEGFA) produced by osteogenically differentiated mesenchymal stem cells (O-MSCs) on the recruitment and regulation of undifferentiated MSCs and macrophages during osteogenesis. Factors secreted from MSCs during osteogenic differentiation were monitored by cytokine arrays. Indirect coculture models were applied to study the effect of VEGFA derived from O-MSCs on the motility, cell morphology and CXCL12/CXCR4 expression in MSCs as well as the regulation of local immune response. A mouse skull defect model was used to unveil the cell recruitment, macrophage activity and new bone formation following O-MSCs transplantation. It was found that VEGFA secretion increased dramatically during the osteogenic differentiation of MSCs. The secreted VEGFA by O-MSCs stimulated the expression of CXCL12/CXCR4, resulting in the recruitment of MSCs and macrophages to the bone defects. It was noted that O-MSCs could regulate the local inflammation by modulating the expression of proinflammatory cytokines in macrophages and neutralizing VEGFA produced by O-MSCs resulted in significant decrease of cell recruitment, cytokine secretion and new bone formation. This study demonstrates that VEGFA secreted by O-MSCs plays a pivotal role in the cell recruitment and regulation of local immune response during osteogenesis.

Strategies to develop endogenous stem cell-recruiting bioactive materials for tissue repair and regeneration

“…Support for this important role has been provided in a study by Zhou et al . where the secretion of VEGF-A was identified as the primary signal responsible for the recruitment of undifferentiated stem cells [153]. It was found that differentiated stem cells can secrete VEGF-A that in turn activates the CXCR4 receptor leading to the recruitment of other stem celland macrophages to the bone defect site.…”

Injectable osteogenic microtissues containing mesenchymal stromal cells conformally fill and repair critical-size defects

“…In this study, OD-MSC were predifferentiated toward the osteogenic lineage using dexamethasone, a regulator of the osteogenic transcription factor Runx2 [44], and βglycerophosphate, a phosphate source for mineralization. It has been shown that similarly predifferentiated MSC interact with macrophages after transplantation to improve defect healing [45]. In addition, priming of MSC toward the osteogenic lineage with potent biochemical factors such as bone morphogenetic protein-2 (BMP-2) [46], platelet-derived growth factor (PDGF) [47], and TNFα [48] prior to transplantation has been shown to be effective in regenerating bone.…”

Co‐transplantation of Wharton's jelly mesenchymal stem cell‐derived osteoblasts with differentiated endothelial cells does not stimulate blood vessel and osteoid formation in nude mice models

“…Furthermore, a growing body of evidence suggests that MSCs have a predominant paracrine role in promoting tissue regeneration (Gnecchi, Danieli, Malpasso, & Ciuffreda, ). The stromal cell‐derived factor 1 (SDF‐1)/C‐X‐C chemokine receptor type 4 (CXCR4) pathway and vascular endothelial growth factor (VEGF) seem to be critical for the migration of cells to injured sites and for subsequent bone and blood vessel formation (Kitaori et al, ; Tu et al, ; Zhou et al, ).…”

“…Moreover, the influence of ECs on OBs has been demonstrated in vivo, where a co‐seeded scaffold gave better bone regeneration and vessel formation (Johari et al, ; Kim SS et al, ). OBs are able to release VEGF (Clarkin, Emery, Pitsillides, & Wheeler‐Jones, ) and set up a microenvironment that recruits host cells to bone defect sites (Zhou et al, ) and can also trigger the angiogenesis process that induces the organization of ECs into a stable vascular network (Fuchs, Hofmann, & Kirkpatrick, ).…”