Abstract
Objective: The regenerative capacity of the heart is very limited and consequently, the heart cannot regenerate adequately after injury. Our previous studies showed that the paracrine factors released from mesenchymal stem cells (MSCs) overexpressing Wnt11 protected cardiomyocytes (CM) after myocardial infarction. Here, we hypothesized that these factors also stimulate CM proliferation. Methods and Results: MSCs harvested from rat bone marrow were transduced with Wnt11 (MSC Wnt11 ) or EGFP empty vector (MSC GFP ). Conditioned medium (CdM ) were obtained from MSC GFP (CdM GFP ) or MSC Wnt11 (CdM Wnt11 ) under normal and hypoxic culture for 36 hours. CM obtained from neonatal and adult rat ventricles were cultured in CdM GFP , CdM Wnt11 or CdM Wnt11-H medium for 3 and 7 days. Cultured CM were stained with BrdU, Ki67, and Aurora B, respectively and identified by staining with α-actinin. Some CM were positive for these proliferative markers ( Fig. 1 ). The expression of proliferating cell nuclear antigen (PCNA), cyclin D2, Nkx2.5, b-myosin heavy chain (b-MHC), atrial natriuretic factor (ANF), troponin I type 1 (Tnni1), troponin I type 3 (Tnni3), sarco-/endoplasmic reticulum Ca 2+ -ATPase (SERCA2), and desmin was analysed ( Fig. 2 ). Although PCNA was downregulated in CM treated with CdM, other cardiac specific markers were significantly upregulated in CM treated with CdM Wnt11 or CdM Wnt11-H obtained from MSC Wnt11 exposed to hypoxia for 24 hours. Moreover, CdM Wnt11 also increased adult CM mitosis, cytokinesis, and CM numbers compared to CdM GFP . In addition, CdM significantly improved the contractile dyskinesis of adult CM caused by 7 days culture in non-serum M199 medium ( Fig. 3 ). Conclusions: Our studies support the hypothesis that paracrine factors released from MSC promote CM re-entry cell-cycle and proliferation. Wnt11 may serve as a positive regulator of CM proliferation.
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