Abstract
Endogenous bone marrow-derived mesenchymal stem cells are mobilized to peripheral blood and injured tissues in response to changes in the expression of various growth factors and cytokines in the injured tissues, including substance P (SP), transforming growth factor-beta (TGF-β), and stromal cell-derived factor-1 (SDF-1). SP, TGF-β, and SDF-1 are all known to induce the migration of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, it is not yet clear how these stimuli influence or interact with each other during BM-MSC mobilization. This study used mouse bone marrow-derived mesenchymal stem cell-like ST2 cells and human BM-MSCs to evaluate whether SP, TGF-β, and SDF-1 mutually regulate their respective effects on the mobilization of BM-MSCs. SP pretreatment of ST2 and BM-MSCs impaired their response to TGF-β while the introduction of SP receptor antagonist restored the mobilization of ST2 and BM-MSCs in response to TGF-β. TGF-β pretreatment did not affect the migration of ST2 and BM-MSCs in response to SP, but downregulated their migration in response to SDF-1. SP pretreatment modulated the activation of TGF-β noncanonical pathways in ST2 cells and BM-MSCs, but not canonical pathways. These results suggest that the migration of mesenchymal stem cells is regulated by complex functional interactions between SP, TGF-β, and SDF-1. Thus, understanding the complex functional interactions of these chemotactic stimuli would contribute to ensuring the development of safe and effective combination treatments for the mobilization of BM-MSCs.
Highlights
Endogenous mesenchymal stem cells are mobilized from the bone marrow to the peripheral blood and peripheral tissues in response to injury [1] or various pathological conditions including tumors [2,3], bone fractures [4], osteoporosis [5], and burns [6]
The injured and pathological tissues secrete various factors such as substance P (SP) [1], transforming growth factor-beta (TGF-β) [7,8,9,10], stromal cell-derived factor-1 (SDF-1) [11], and hepatocyte growth factor (HGF) [12], which induce the mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs)
As previously demonstrated [8,13], SP and TGF-β induce the chemotactic migration of ST2 cells and when compared to the control, SP and TGF-β stimulation increase the migration of ST2 cells by 4.6-fold and 2.7-fold, respectively (Figure S1A–D)
Summary
Endogenous mesenchymal stem cells are mobilized from the bone marrow to the peripheral blood and peripheral tissues in response to injury [1] or various pathological conditions including tumors [2,3], bone fractures [4], osteoporosis [5], and burns [6]. Smad protein-dependent signaling is the canonical pathway for TGF-β signaling but TGF-β transduces signals via ERKs, Akt, and p38, independently of Smad (noncanonical pathway) [15] Both the canonical and noncanonical pathways are required for the migration of BM-MSCs [8]. Understanding the combined effects of various factors on the mobilization of BM-MSCs is essential in determining the final level and mobilization kinetics of BM-MSCs to injured tissues It is still unclear whether the various factors can modulate their respective mobilization capacities to fine-tune the mobilization of BM-MSCs. SP, TGF-β, or SDF-1 can be applied to prime BM-MSCs for migration to enhance or maintain the therapeutic potential of these cells [18,19]. We used murine bone marrow-derived mesenchymal stem cell-like cells (ST2 cells) and human BM-MSCs to evaluate whether SP, TGF-β, and SDF-1 mutually regulate their respective BM-MSC migration-promoting abilities
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