Wnt signalling: a mediator of the heart-bone marrow axis after myocardial injury?

This editorial refers to ‘Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow’†, by B. Assmus et al., on page 1911 The last decade has been a very productive period for innovative developments of cell-based therapy as an alternative and promising treatment strategy for heart disease due to ischaemic injury. There is accumulating evidence that substantial cardiac repair can be achieved in small1 and large2−4 animal models as well as humans,5−7 using either whole bone marrow (BM) mononuclear cells or specific BM constituents, including ex vivo cultured BM-derived mesenchymal stem cells (MSCs). 6,7 From a clinical perspective, studies have examined the efficacy of cell-based therapy in the settings of both acute myocardial infarction (MI) and chronic ischaemic cardiomyopathy.5,6 Cell therapy could lead to successful cardiac regeneration or repair by any of four general mechanisms: differentiation of the administered cells into cardiac, endothelial, vascular smooth muscle, and/or other cells of the heart; release of antifibrotic, proangiogenic, and trophic paracrine factors from the administered cells; fusion of the administered cells with the existing cellular constituents of the heart; and induction of endogenous repair through stimulation of resident cardiac stem cell (CSC) proliferation and differentiation.2,6,8 Regardless of the mechanism, cell therapy has improved heart function after ischaemic injury in numerous studies. In porcine models of MI, autologous MSCs produced substantial structural (reduced infarct size) and functional (increased regional contractility and myocardial blood flow) reverse remodelling,4 while allogeneic MSCs were able to engraft and undergo trilineage differentiation into cardiac, vascular muscle, and endothelial cells3,9 as well as stimulate host CSC proliferation and differentiation.2 However, there are inconsistencies in the results among animal experiments and clinical trials, which might be related to the varied number of stem cell sources, isolation and delivery methods, as well as type and method of assessment of clinical endpoints. Moreover, the limited capability of injected cells to engraft and survive in the injured tissue remains a significant therapeutic challenge. Therefore, strategies to augment stem cell proliferation, differentiation, homing, and survival are crucial to improving the efficacy of cell-based therapies.10 In this regard, various growth factors and chemokines have been shown to promote stem cell signalling, survival, and homing to the injured myocardium.10 Another consideration is the timing of cell injection after acute MI. A systematic analysis of seven clinical trials which studied intracoronary BM stem cell therapy reported that treatment at 4–7 days post-MI is superior to that within 24 h in terms of improvement in left ventricular (LV) ejection fraction, decrease in LV end-systolic dimension, and reduction in the incidence of revascularization. The authors proposed that the superior effects of BM stem cell therapy given at 4–7 days might be linked to a more favourable myocardial microenvironment than during the first 24 h post-MI.11 Changes in the microenvironment might be the result of the growth factor/chemokine release after acute MI, which may favour the heart's receptivity for stem cell engraftment, survival, and differentiation and/or stimulation of host CSCs to protect or repair myocardial structure and function, thus preventing remodelling preferentially during that window of time. In addition, this burst of factors released into the peripheral blood may affect not only the myocardium but also BM metabolism and function. Indeed, activation of BM niches that release various types of haematopoietic stem cells (HSCs) into the circulating blood during acute MI has been shown previously.12 The article by Assmus et al.13 has demonstrated in patients from the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) and the Reinfusion of Enriched Progenitor cells And Infarct Remodeling In Acute Myocardial Infarction (REPAIR-AMI) trials that the metabolic activity of BM is augmented after acute MI, accompanied by a time-dependent increase in the number of resident CD34+ and CD133+ HSCs within 7 days post-MI. This increased BM proliferation rate post-MI may contribute to the replenishment of mobilized HSCs. Similarly, using a murine model of acute MI, the study by Assmus et al. shows a robust mobilization of c-Kit+-Sca-1+-Lineage− (KSL) cells into the peripheral circulation post-MI, consistent with previous reports.12 Importantly, Assmus et al. also demonstrate an MI-induced activation of canonical Wnt signalling in the BM, associated with expansion and migration of HSCs.13 Beyond this exciting finding, the complexity of Wnt signalling may hinder an easy identification of the mechanisms linking cardiac events and BM response. Wnt comprises a large family of signalling proteins that initiate both canonical and non-canonical pathways and are strongly influenced by a multitude of cytokines and small molecules in the tissue microenvironment. Activation of non-canonical Wnt pathways can play an inhibitory role in canonical signalling.14 On the other hand, constitutive activation of canonical Wnt signalling has been shown to inhibit multilineage differentiation of HSCs and also self-renewal in BM.15 However, it is widely accepted that a regulated transient canonical Wnt pathway might conserve stemness and functionality of BM HSCs. Although Assmus et al. did not investigate the mechanism leading to activation of Wnt signalling, they demonstrated that the canonical pathway is activated in BM since LEF/TCF/β-catenin-responsive promoter activation was observed in their experimental model. Moreover, the canonical agonist Wnt3a stimulated proliferation and migration of human BM-derived mononuclear cells ex vivo. Since catecholaminergic stimulation of Wnt in BM has been previously demonstrated,16 the authors propose the release of catecholamines post-MI as mediators in the heart–BM axis (Figure 1). Figure 1 Heart–bone marrow axis after acute myocardial infarction (AMI). Hypothetical interaction between the myocardium and bone marrow (BM) within 7 days post-AMI. Growth factors/cytokines/hormones activated and released after AMI activate canonical .