A mechanism of mesenchymal stem cell-mediated cardiac repair

22 23 24 We recently demonstrated a cardiac therapeutic regimen based on injection of bone 25 marrow mesenchymal stem cells (MSCs) into the skeletal muscle. Although the injected MSCs 26 were trapped in the local musculature, the extracardiac cell delivery approach repaired the 27 failing hamster heart. This finding uncovers a tissue repair mechanism mediated by trophic 28 factors derived from the injected MSCs and local musculature that can be explored for minimally 29 invasive stem cell therapy. However, the trophic factors involved in cardiac repair and their 30 actions remain largely undefined. We demonstrate here a role of MSC-derived IL-6-type 31 cytokines in cardiac repair through engagement of the skeletal muscle JAK/STAT3 axis. The 32 MSC IL-6-type cytokines activated JAK/STAT3 signaling in cultured C2C12 skeletal myocytes 33 and caused increased expression of the STAT3 target genes HGF and VEGF, which was 34 inhibited by gp130 blockade. These in vitro findings were corroborated by in vivo studies, 35 showing that the MSC-injected hamstrings exhibited activated JAK/STAT3 signaling and 36 increased growth factor/cytokine production. Elevated host tissue growth factor levels were also 37 detected in quadriceps, liver, and brain, suggesting a possible global trophic effect. Paracrine 38 actions of these host tissue-derived factors activated the endogenous cardiac repair 39 mechanisms in the diseased heart mediated by AKT, ERK, and JAK/STAT3. Administration of 40 the cell-permeable JAK/STAT inhibitor WP1066 abrogated MSC-mediated host tissue growth 41 factor expression and functional improvement. The study illustrates that the host tissue trophic 42 factor network can be activated by MSC-mediated JAK/STAT3 signaling for tissue repair. 43 44 45