Transforming growth factor β induces bone marrow mesenchymal stem cell migration via noncanonical signals and N‐cadherin

Abstract

Transforming growth factor‐beta (TGF‐β) induces the migration and mobilization of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) to maintain bone homeostasis during bone remodeling and facilitate the repair of peripheral tissues. Although many studies have reported the mechanisms through which TGF‐β mediates the migration of various types of cells, including cancer cells, the intrinsic cellular mechanisms underlying cellular migration, and mobilization of BM‐MSCs mediated by TGF‐β are unclear. In this study, we showed that TGF‐β activated noncanonical signaling molecules, such as Akt, extracellular signal‐regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, via TGF‐β type I receptor in human BM‐MSCs and murine BM‐MSC‐like ST2 cells. Inhibition of Rac1 by NSC23766 and Src by PP2 resulted in impaired TGF‐β‐mediated migration. These results suggested that the Smad‐independent, noncanonical signals activated by TGF‐β were necessary for migration. We also showed that N‐cadherin‐dependent intercellular interactions were required for TGF‐β‐mediated migration using functional inhibition of N‐cadherin with EDTA treatment and a neutralizing antibody (GC‐4 antibody) or siRNA‐mediated knockdown of N‐cadherin. However, N‐cadherin knockdown did not affect the global activation of noncanonical signals in response to TGF‐β. Therefore, these results suggested that the migration of BM‐MSCs in response to TGF‐β was mediated through N‐cadherin and noncanonical TGF‐β signals.

Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

“…Additionally, some studies have demonstrated that TGF-β1 is capable of inducing the mobilization and migration of BM-MSC to bone remodeling. N-cadherin-mediated intercellular interactions and noncanonical signaling molecules activated through TGF-β type I receptor, such as Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, are required to increase the migration capacity of MSC [ 55 ].…”

Friend or Foe? Essential Roles of Osteoclast in Maintaining Skeletal Health

“…During bone remodeling and fractured-bone regeneration, MSCs migrate to the bone surface or fracture site and then differentiate into OBs to reconstruct the bone [76], subsequent to the osteoclastic resorptive phase. It has been well demonstrated that local growth factors and signals play important roles in the recruitment and commitment of MSCs [77], such as the bone morphogenetic protein (BMP) family [78], insulin-like growth factor (IGF) [79,80], TGF-β [68,81], fibroblast growth factor 2 (FGF-2) [82], vascular endothelial growth factors (VEGF) [78], and platelet-derived growth factors (PDGFs) [83,84]. Moreover, emerging evidence showed that many of these local factors are associated with the viability and activity of OCs [17,20,54].…”

Attachment and spatial organisation of human mesenchymal stem cells on poly(ethylene glycol) hydrogels

“…Platelet derived growth factor (PDGF) [70,71] CXC chemokines (especially SDF-1α) [72][73][74][75][76] Vascular endothelial growth factor (VEGF) [77] Tumor necrosis factor alpha (TNF-α) [78] Transforming growth factor beta (TGF-β) [79,80] Matrix metalloproteinases (MMP) [81,82] Granulocyte-colony-stimulating factor (G-CSF) [83,84] Unfortunately, bolus systemic or local injections of growth factors (GFs) have low stability and undergo rapid degradation with limited half-lives in vivo [85][86][87]. Alternatively, repeated doses of these factors can have adverse systemic effects, along with unnecessary accumulation across the body [88].…”