Abstract 12807: Leptin Signaling is Required for Augmented Therapeutic Properties of Mesenchymal Stem Cells Conferred by Hypoxia
Background: The beneficial effects of stem cell hypoxic preconditioning (HPC) prior to treatment of acute myocardial infarction (AMI) have been confirmed in multiple studies that describe enhanced cell survival, homing and therapeutic outcome. Enhanced SDF-1/CXCR4 has been implicated as part of the HPC pathway.
Hypothesis: Leptin is induced by HPC, positively regulates SDF-1/CXCR4 through STAT3 and is required for enhanced cell therapy.
Methods: Human or mouse bone marrow derived mesenchymal cells (MSCs) were subject to HPC by 24h exposure to hypoxia (pO2 ~ 4 mmHg). The effects of HPC and role for leptin were determined by quantitative co-culture-cytoprotection and migration (Boden Chamber) assays, and in vivo using mouse AMI models with leptin/leptin-receptor (LEPR) loss of function transgenic mice and direct intracardiac cell delivery.
Results: In vitro HPC-enhanced functions included cell survival under simulated ischemia, cytoprotection of co-cultured cardiac myocytes, and cell mobilization (all p≤0.05; n=4). All effects of HPC were abolished by knockdown of leptin with a selective shRNA and were absent in MSCs from ob/ob (Lep deficient) or db/db (LepR deficient) mice (all p≤0.05; n=4). The positive effects were paralleled by increased expression of leptin (>50-fold mRNA; >8-fold protein; p≤0.05, n=4), its target transcription factor STAT3 (1.9-fold increase, p≤0.05) and cell surface receptor CXCR4 (1.7-fold increase surface expression; p≤0.05; n=4). Cell therapy using MSCs derived from wild type, ob/ob, or db/db mice was implemented in a mouse AMI model. Augmented protection by HPC was only seen with MSCs from wild type mice. Parameters that were differentially affected by HPC included MSC engraftment, c-Kit+ cell recruitment to the infarct, vascular density, infarct size and long-term contractile function (all p≤0.05; n=4-6).
Conclusions: The results show that leptin signaling is essential for the enhanced survival, chemotaxis, and therapy conferred on MSCs by HPC. The mechanism may include STAT3-enhanced HIF-1α-mediated induction of the SDF-1/CXCR4. Leptin may prime MSCs resident in the hypoxic niche of the bone marrow endosteum for optimal response to systemic signaling molecules and subsequent migration and tissue repair.
- © 2013 by American Heart Association, Inc.