Abstract 18986: Unopposed TNF/TNFR1 Signaling Prevents Therapeutic Benefit From Cardiac Stem Cell Therapy After Reperfused Myocardial Infarction in Mice
Despite expansion of resident cardiac stem cells (CSCs) after myocardial infarction (MI), the heart is unable to regenerate, suggesting that local factors inhibit CSC function. Tumor necrosis factor-α (TNF), increased in infarcted and failing hearts, is one candidate inhibitory factor; its effects are specific to its two receptors (TNFRs). We hypothesized that TNF/TNFR signaling in CSCs modulates the efficacy of CSC therapy after reperfused MI in mice. Magnetically sorted, c-kit enriched, Lin– CSCs were isolated from wild-type (WT), TNFR1-/-, and TNFR2-/- mice, expanded, and 1 x 105 CSCs were administered via intramyocardial injection in the border zone 48 h after 60 min ischemia in WT C57BL/6 mice (n = 13-18/group). Five weeks after CSC therapy, as compared with PBS-injected MI mice, WT CSC transplantation significantly (p<0.05) improved LV systolic function (ESV 50 ± 14 vs 63 ± 23 μL; EF 31 ± 11 vs 24 ± 9%). Analogous to WT CSCs, TNFR1-/- CSCs also significantly improved LV systolic function (ESV 44 ± 5 uL; EF 35 ± 3%). In contrast, TNFR2-/- CSC transplanted MI hearts exhibited greater LV systolic dysfunction (ESV 62 ± 5 uL; EF 29 ± 4%) as compared with both WT and TNFR1-/- CSC injected hearts, and were comparable to PBS-injected MI hearts. There was signficantly reduced border zone (BZ) fibrosis in both WT (7.6 ± 3.2%) and TNFR1-/- CSC (7.2 ± 1.9%) injected hearts as compared with either PBS-injected MI hearts (11.6 ± 2.8%), or TNFR2-/- CSC injected MI hearts (15.7 ± 4.0%). Analogous to fibrotic change, cardiomyocyte hypertrophy in post-MI hearts was significantly decreased after cell transplantation with either WT CSCs (322 ± 56 μm2) or TNFR1-/- CSCs (244 ± 29 μm2), as compared with PBS-injected MI hearts (423 ± 56 μm2), with more robust improvements in hypertrophy in the TNFR1-/- CSC MI hearts. In contrast, cardiomyocyte size after TNFR2-/- CSC transplantation (389 ± 58 μm2) was comparable to PBS injected hearts, and significantly greater than either WT or TNFR1-/- CSC injected MI hearts. We conclude that myocardial TNF diminishes the efficacy of CSC therapy via TNFR1 signaling, especially when unopposed by concomitant TNFR2 signaling. Selective TNFR1 blockade, or TNFR2 agonism, at the time of cell transplantation may improve the functional outcomes of CSC therapy after MI.
Author Disclosures: T. Hamid: None. Y. Xu: None. M.A. Ismahil: None. M. Goel: None. B. Patel: None. A.M. Michaud: None. Q. Li: None. A. Bhatnagar: None. R. Bolli: None. S.D. Prabhu: None.
- © 2015 by American Heart Association, Inc.