Mesenchymal stem cells (MSCs) may improve myocardial function after I/R injury via paracrine effects, including the release of
growth factors. Genetic modification of MSCs is an appealing method to enhance MSC paracrine action. Ablation of
TNF receptor 1 (
TNFR1), but not
TNFR2, increases MSC
growth factor production. In this study, therefore, we hypothesized that 1) preischemic infusion of MSCs derived from
TNFR1 knockout (TNFR1KO) mice will further improve myocardial functional recovery and that 2) TNFR2KO and
TNFR1/2KO will abolish MSC-mediated protection in the heart after I/R injury. Mesenchymal stem cells were harvested from adult C57BL/6J (wild-type 1 [WT1]), B6129SF2 (WT2), TNFR1KO, TNFR2KO, and
TNFR1/2KO mice. Mesenchymal stem cells were cultured and adopted for experiments after passage 3. Isolated hearts from adult male Sprague-Dawley rats were subjected to 25 min of
ischemia and 40 min of reperfusion (Langendorff model), during which time myocardial function was continuously monitored. Before
ischemia, 1 mL of vehicle or 1 x 10(6) MSCs/mL from WT1, WT2, TNFR1KO, TNFR2KO, or
TNFR1/2KO was infused into the hearts (n = 4-6 per group). Treatment of C57BL/6J mice with MSC before
ischemia significantly increased cardiac function.
TNFR1 knockout MSCs demonstrated greater cardioprotection when compared with WT MSCs after I/R, as exhibited by improved left ventricular developed pressure and +/-dp/dt. However, infusion of MSCs from TNFR2KO and
TNFR1/2KO mice either offered no benefit or decreased MSC-mediated cardiac functional recovery in response to I/R when compared with WT MSCs.
TNFR1 signaling may damage MSC paracrine effects and decrease MSC-mediated cardioprotection, whereas
TNFR2 likely mediates beneficial effects in MSCs.