Abstract
BackgroundParacrine signaling from endothelial progenitor cells (EPCs) is beneficial for angiogenesis and thus promotes tissue regeneration. Microgravity (MG) environment is found to facilitate the functional potentials of various stem or progenitor cells. The present study aimed to elucidate the effects of MG on pro-angiogenic properties and fracture repair capacities of conditioned media (CM) from EPCs.MethodsHuman peripheral blood-derived EPCs were cultured under MG or normal gravity (NG) followed by analysis for angiogenic gene expression. Furthermore, the serum-free CM under MG (MG-CM) or NG (NG-CM) were collected, and their pro-angiogenic properties were examined in human umbilical vein endothelial cells (HUVECs). In order to investigate the effects of MG-CM on fracture healing, they were injected into the fracture gaps of rat models, and radiography, histology, and mechanical test were performed to evaluate neovascularization and fracture healing outcomes.ResultsMG upregulated the expression of hypoxia-induced factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) and promoted NO release. Comparing to NG-CM, MG-CM significantly facilitated the proliferation, migration, and angiogenesis of HUVECs through NO-induced activation of FAK/Erk1/2-MAPK signaling pathway. In addition, MG-CM were verified to improve angiogenic activities in fracture area in a rat tibial fracture model, accelerate fracture healing, and well restore the biomechanical properties of fracture bone superior to NG-CM.ConclusionThese findings provided insight into the use of MG bioreactor to enhance the angiogenic properties of EPCs’ paracrine signals via HIF-1α/eNOS/NO axis, and the administration of MG-CM favored bone fracture repair.Graphical abstract
Highlights
Paracrine signaling from endothelial progenitor cells (EPCs) is beneficial for angiogenesis and promotes tissue regeneration
MG-conditioned media (CM) facilitated human umbilical vein endothelial cells (HUVECs)’ proliferation, migration, and angiogenesis in vitro The in vitro experiments were performed in HUVECs
The matrigel tube formation assay was employed to detect the angiogenic capacities of HUVECs, and the results suggested that nitric oxide (NO) partially contributed to the enhanced angiogenic potential of MG-CM as revealed by total tube length (Fig. 3h, i)
Summary
Paracrine signaling from endothelial progenitor cells (EPCs) is beneficial for angiogenesis and promotes tissue regeneration. Microgravity (MG) environment is found to facilitate the functional potentials of various stem or progenitor cells. The present study aimed to elucidate the effects of MG on pro-angiogenic properties and fracture repair capacities of conditioned media (CM) from EPCs. Bone fracture caused mainly by accidents or sports injuries is a common clinical emergency [1]. Treatment means exploration for accelerating bone regeneration is needed to relieve this predicament. Formed blood vessels are in charge of transporting oxygen, nutrients, numerous cell types, and cytokines to the injury site for tissue repair. The importance of modulating vascularization at fracture sites for better fracture healing is widely accepted as a new treatment option which is under extensive investigation
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