Platelet-Rich Plasma Greatly Potentiates Insulin-Induced Adipogenic Differentiation of Human Adipose-Derived Stem Cells Through a Serine/Threonine Kinase Akt-Dependent Mechanism and Promotes Clinical Fat Graft Maintenance
Open Access
- 1 March 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Stem Cells Translational Medicine
- Vol. 1 (3), 206-220
- https://doi.org/10.5966/sctm.2011-0052
Abstract
The potential plasticity and therapeutic utility in tissue regeneration of human adipose-derived stem cells (ASCs) isolated from adult adipose tissue have recently been highlighted. The use of autologous platelet-rich plasma (PRP) represents an alternative strategy in regenerative medicine for the local release of multiple endogenous growth factors. Here we investigated the signaling pathways and effects of PRP and human recombinant insulin on proliferation and adipogenic differentiation of ASCs in vitro. PRP stimulated proliferation (EC50 = 15.3 ± 1.3% vol/vol), whereas insulin's effect was the opposite (IC50 = 3.0 ± 0.5 μM). Although PRP alone did not increase adipogenesis, in association with insulin it prevented ASC proliferative arrest, greatly enhanced intracytoplasmic lipid accumulation, strongly increased serine/threonine kinase Akt phosphorylation and mouse monoclonal anti-sterol regulatory element binding protein-1 accumulation, and downregulated Erk-1 activity; adipogenic effects were markedly prevented by the Akt inhibitor wortmannin. PRP with insulin synergistically upregulated fibroblast growth factor receptor (FGFR) and downregulated epidermal growth factor receptor (ErbB) expression; moreover, PRP in association prevented insulin-induced insulin-like growth factor-1 receptor and insulin receptor downregulation. The inhibition of FGFR-1, epidermal growth factor receptor (EGFR), and epidermal growth factor receptor-2 (ErbB2) activity reduced ASC proliferation, but only that of FGFR-1 reduced adipogenesis and Akt phosphorylation, whereas the ErbB2 inhibition effects were the opposite. However, EGFR activity was needed for ErbB2-mediated inhibition of ASC adipogenesis. Clinically, the injection of insulin further ameliorated patients' 1-year PRP-induced fat graft volume maintenance and contour restoring. Our results ascertain that PRP in association with insulin greatly potentiates adipogenesis in human ASCs through a FGFR-1 and ErbB2-regulated Akt mechanism. The ameliorated clinical fat graft maintenance suggests additional useful translational applications of combined PRP-insulin treatment in regenerative medicine.Keywords
This publication has 56 references indexed in Scilit:
- Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene TranscriptionJournal of Biological Chemistry, 2010
- Buffered Platelet-Rich Plasma Enhances Mesenchymal Stem Cell Proliferation and Chondrogenic DifferentiationTissue Engineering, Part C: Methods, 2009
- Culture effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on cryopreserved human adipose-derived stromal/stem cell proliferation and adipogenesisJournal of Tissue Engineering and Regenerative Medicine, 2009
- The FGF family: biology, pathophysiology and therapyNature Reviews Drug Discovery, 2009
- Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interfaceNature, 2007
- Down‐modulation of erbB2 activity is necessary but not enough in the differentiation of 3T3‐L1 preadipocytesJournal of Cellular Biochemistry, 2007
- AKT/PKB Signaling: Navigating DownstreamCell, 2007
- EGF–ERBB signalling: towards the systems levelNature Reviews Molecular Cell Biology, 2006
- The Immunogenicity of Human Adipose‐Derived Cells: Temporal Changes In VitroThe International Journal of Cell Cloning, 2006
- Apoptosis in the rat brown adipose tissue after insulin treatmentJournal of Thermal Biology, 1999