Abstract 14198: Pre-Conditioning of Stem Cell With Celastrol to Enhance Their Therapeutical Potential
Background: Stem cell transplantation is a potential approach to repopulate the injured myocardium and restore function. Cellular therapy is limited by several issues including cell scarcity, survival and faith of the implanted cells. Most cells die within hours of transplantation because of interaction of ischemia, inflammation, and apoptosis. The objective is to investigate a novel strategy using a simple ex vivo pharmacologic pre-conditioning of stem cells with Celastrol, a triterpenoid antioxidant compound.
Methods & Results: Rat mesenchymal stem cells (MSC) were isolated from the bone marrow and expanded. MSC were shortly exposed to various concentrations of Celastrol, but 10-6M provided maximum stimulation of cells without effects on cell viability at 24-48hrs of culture. We observed a dramatic and rapid activation of the PI3K/Akt and p44/42 MAPK (ERK1/2) pathways, see Figure. Several effectors and important genes involved in cellular protection and survival were up regulated: Hif1a, HO-1 (HSP32), HSP27, HSP70 and VEGF. We also observed an increase in Heat shock factor protein 1 (Hsf1) expression and its translocation from the cytoplasm to the nucleus. Celastrol significantly improved MSC viability with an increase in survival under hypoxic and serum starvation conditions, and protected against oxidative stress with H2O2.
Conclusion: We propose a Celastrol pre-treatment of MSC before their engraftment in vivo to enhance their reparative potential. We demonstrated a rapid activation of kinases involved in many cellular programs such as cell proliferation, differentiation, motility, and survival. Celastrol activated the heat shock response through Hsf1 and HSPs, and preserved MSC from hypoxic and oxidative cell death. The novelty of our study is to combine a simple pharmacological treatment to cell therapy, which can be applied to various cell type prior to transplantation, and without systemic effects or genetic modification.
- © 2011 by American Heart Association, Inc.