Abstract
Bone marrow-derived mesenchymal stem cells (BMMSCs) are used extensively for cardiac repair and interact with immune cells in the damaged heart. Macrophages are known to be modulated by stem cells, and we hypothesized that priming macrophages with BMMSCs would enhance their therapeutic efficacy. Rat bone marrow-derived macrophages (BMDMs) were stimulated by lipopolysaccharide (LPS) with or without coculture with rat BMCs. In the LPS-stimulated BMDMs, induction of the inflammatory marker iNOS was attenuated, and the anti-inflammatory marker Arg1 was markedly upregulated by coculture with BMMSCs. Myocardial infarction (MI) was induced in rats. One group was injected with BMMSCs, and a second group was injected with MIX (a mixture of BMMSCs and BMDMs after coculture). The reduction in cardiac fibrosis was greater in the MIX group than in the BMC group. Cardiac function was improved in the BMMSC group and was substantially improved in the MIX group. Angiogenesis was better in the MIX group, and anti-inflammatory macrophages were more abundant in the MIX group than in the BMMSC group. In the BMMSCs, interferon regulatory factor 5 (IRF5) was exclusively induced by coculture with macrophages. IRF5 knockdown in BMMSCs failed to suppress inflammatory marker induction in the macrophages. In this study, we demonstrated the successful application of BMDMs primed with BMMSCs as an adjuvant to cell therapy for cardiac repair.
Highlights
To date, inducing cardiac regeneration using stem cells has remained tremendously challenging
Coculture with Rat BMMSCs (rBMMSCs) reduced the mRNA induction of proinflammatory genes, including iNOS, TNF-α, and IL-1β, whereas the anti-inflammatory Arg[1] mRNA was upregulated in the LPS-stimulated rBMDMs (Fig. 1a)
Arg[1], CD206 and IL-10 were highly induced by culture of the IL-4/IL13-treated rBMDMs with the rBMMSCs (Fig. 1b)
Summary
To date, inducing cardiac regeneration using stem cells has remained tremendously challenging. Bone marrowderived mesenchymal stem cells (BMMSCs) are regarded as an attractive option for cardiac regeneration therapy[1]. BMMSCs are relatively easy to isolate and can differentiate into mesenchymal lineage cell types, such as osteocytes, chondrocytes, adipocytes, and myocytes[2]. MSCs have the immunoprivileged capacity to avoid rejection, suppress inflammation in the lesion, and modulate immune cell phenotypes[3]. Despite the safety and feasibility of BMMSCs, concerns over their use Macrophages are highly dynamic immune cells with diverse functions and are widely involved in the pathogenesis of cardiovascular diseases, including myocardial infarction (MI) and atherosclerosis. Anti-inflammatory macrophages are essential for inducing infarct healing, because depletion of cardiac macrophages drastically impairs healing and worsens the disease outcome[9]. Infarct healing and repair by BMMSCs is mediated by macrophages[10]
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