Cardioprotective molecular mechanisms underlying adult bone marrow progenitor cell therapy have not been fully elucidated. We hypothesized that intravenous bone marrow mononuclear cells (BMMNC) might be:
protective when administered upon reperfusion
protective by paracrine mechanisms.
Freshly isolated 10 million BMMNC,
c-Kit
+
(7 ± 1%, n =10),
CD34
+
(7 ± 1%, n =10),
CD45
+
(54 ± 6 %, n = 10), and
CD133
+
(15 ± 1%, n = 10), were intravenously administered upon reperfusion in a rat model of 25 minutes left anterior descending coronary artery occlusion followed by reperfusion lasting either 2 hours (I/R2h) or 7 days (I/R7D). At the end of I/R2h, BMMNC caused significant reductions in infarct size (BMMNC 33 ± 3 %; control 57 ± 2 %, n = 10, P < 0.01). Following I/R7D, BMMNC caused significant improvements in systolic function (LVEF: BMMNC 71 ± 3 %; control 48 ± 4 %, n = 11, P < 0.0001) and diastolic function (LVEDP: BMMNC 5 ± 2 mmHg; control 15 ± 2 mmHg, n = 9, P < 0.01). Comparable cardioprotection was achieved when BMMNC supernatant was intravenously administered instead of BMMNC. Cardioprotection by BMMNC was associated with Akt phosphorylation, which could be abolished by inhibition of PI3K with LY294002. When compared with controls, proteomics of hearts subjected to I/R2h and treated with BMMNC demonstrated higher expression of
the anti-oxidants catalase (3.3 fold), and peroxiredoxin 6 (2.0 fold);
heat shock proteins HSP20 (2.9 fold), alpha B crystallin (1.7 fold), HSP72 (2.8 fold), ischemia responsive protein-94 (1.6 fold), and TNF receptor-associated protein 1 (2.3 fold);
glycolytic enzymes alpha-enolase (1.6 fold), glyceraldehyde-3-phosphate dehydrogenase (2 fold), and pyruvate kinase (2 fold); and
mitochondrial respiratory proteins, aconitase (4.8 fold), ATPase synthase (3.5 fold), citrate synthase (2.5 fold), and voltage-dependent anion-selective channel protein 1 (3.4 fold).
In conclusion, intravenous administration of BMMNC upon reperfusion reduced infarct size by activation of the PI3K/Akt survival pathway. Further survival benefits were also demonstrated by up-regulated expression of recognised cardioprotective anti-oxidants, heat shock proteins, and augmented glycolytic mitochondrial bioenergetics.
Pelleted Bone Marrow Derived Mesenchymal Stem Cells Are Better Protected from the Deleterious Effects of Arthroscopic Heat Shock
