Resident Cardiac Stem Cells (RCSCs) enhance myocardial repair in ischemic heart when modified with Wnt16 — ASN Events
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Resident Cardiac Stem Cells (RCSCs) enhance myocardial repair in ischemic heart when modified with Wnt16 (#410)

Jason Seow 1 , Anthony Gill 2 , Christopher Jackson 3 , Stephen Hunyor 1
  1. Cardiac Technology Centre , Kolling Institute of Medical Research, Sydney, New South Wales, Australia
  2. Bill Walsh Cancer Research, Kolling Institute of Medical Research , Sydney , New South Wales , Australia
  3. Sutton Arthritis Research Laboratories , Kolling Institute of Medical Research, Sydney, New South Wales, Australia

Secreted Wnt molecules are involved in regulating morphogenesis and cardiogenesis (Wnt16>Wnt5>Wnt3) in CD117+/LIN- cardiac stem cells (RCSC) via canonical or non-canonical signalling. We found enhanced expression of cardiac transcription factors and structural molecules e.g. GATA4, cTnT and a-s-actinin in Wnt16 co-cultured RCSC. This study provides evidence of the cardiac reparative properties of Wnt16 expressing-RCSC involving matrix metalloproteinases (MMP) and their inhibitors (TIMP).

Methods: Wnt16-GFP-RCSC transfection efficiency was confirmed with flow-cytometry (FC), immuno–blotting (IB) and -fluorescence. Rats were divided into 3 groups (media control, untreated RCSC and Wnt16-GFP-RCSC, n=5/group). Hearts were exposed to 30min ischemia before injection of ~1x106 cells 2 mm apart, into infarct-border zone (BZ),  followed by harvesting at 48h and 4w for histology and assay of cardio-protective, pro-apoptotic and tissue remodelling factors.

Results: FC showed 96.23±0.5% of Wnt16-GFP-RCSC as Wnt16+. At 48h, hearts injected with these cells had smaller infarcts compared to media control (ischemic area 30.8+/-1.4%, infarct 17.9+/-1.9% of LV vs 50.8+/-2.7%, 37.9+/-3.9%, p<0.05). At 4w, Sirius red LV fibrotic area was 20+/-1.35% with Wnt16-GFP-RCSC, 35+/-1.8% with untreated RCSC and 52+/-2.1% in media control (p<0.05). Wnt16-GFP-RCSC treatment showed elevated expression of TIMP-1 and -4 (2.5- and 3.6 fold increase), and down-regulation of MMP-2, -3, and -9 (1.3, 6.2, and 4.8 fold).  Significant increase of pro-apoptotic molecules (Bcl-2 and Bax), angiogenic (Flk-1 and VEGF) and cardio-protective factors (phos-GSK3b and NF-kappab) was shown on IB.

Conclusion: Wnt16-expressing RCSC showed enhanced reparative effects in ischemic hearts by increasing angiogenic, pro-apoptotic and cardio-protective molecules, and by regulating tissue remodelling factors.