Priming with a Combination of FGF2 and HGF Restores the Impaired Osteogenic Differentiation of Adipose-Derived Stem Cells

Abstract

Classical aging-associated diseases include osteoporosis, diabetes, hypertension, and arthritis. Osteoporosis causes the bone to become brittle, increasing fracture risk. Among the various treatments for fractures, stem cell transplantation is currently in the spotlight. Poor paracrine/differentiation capacity, owing to donor age or clinical history, limits efficacy. Lower levels of fibroblast growth factor 2 (FGF2) and hepatocyte growth factor (HGF) are involved in cell repopulation, angiogenesis, and bone formation in the elderly ADSCs (ADSC-E) than in the young ADSCs (ADSC-Y). Here, we study the effect of FGF2/HGF priming on the osteogenic potential of ADSC-E, determined by calcium deposition in vitro and ectopic bone formation in vivo. Age-induced FGF2/HGF deficiency was confirmed in ADSCs, and their supplementation enhanced the osteogenic differentiation ability of ADSC-E. Priming with FGF2/HGF caused an early shift of expression of osteogenic markers, including Runt-related transcription factor 2 (Runx-2), osterix, and alkaline phosphatase (ALP) during osteogenic differentiation. FGF2/HGF priming also created an environment favorable to osteogenesis by facilitating the secretion of bone morphogenetic protein 2 (BMP-2) and vascular endothelial growth factor (VEGF). Bone tissue of ADSC-E origin was observed in mice transplanted with FGF/HGF-primed ADSC-E. Collectively, FGF2/HGF priming could enhance the bone-forming capacity in ADSC-E. Therefore, growth factor-mediated cellular priming can enhance ADSC differentiation in bone diseases and thus contributes to the increased efficacy in vivo.