Schematic diagram of strategies for site-targeted imaging of stem/progenitor cells using contrast-enhanced ultrasound (CEU)
With the rapid progression of research into stem or progenitor cell therapy, there is a growing need to develop imaging modalities to track progenitor cells in vivo after their delivery. The ability to track delivered cells using contrast-enhanced ultrasound (CEU) has only been recently investigated. This schematic diagram shows the potential strategies for CEU-targeted imaging of stem/progenitor cells, such as endothelial progenitor cells (EPCs). One strategy involves alteration/transfection of EPCs to express a specific marker protein on the cell surface. Microbubbles (MB) targeted to engrafted EPCs could be constructed by the attachment of the ligand/antibody targeted against the specific cell surface marker protein on the microbubble surface (left panel, inset). When this EPC-targeted MB is administered intravenously, the MBs circulate to target sites where they can bind to EPCs that are engrafted within the vasculature and subsequently be imaged by CEU imaging techniques. The other described strategy involves manipulating EPCs to fully engulf MB prior to cell delivery. Once delivered and engrafted, ultrasonic imaging could then detect MBs present and retained within engrafted EPCs (right panel, inset). Future work will likely focus on 1) the refinement of these two strategies; 2) pre-clinical testing in relevant animal models of disease, and 3) the development of new techniques for progenitor cell-targeted CEU imaging.
Abbreviations: MB – microbubble; EPC – endothelial progenitor cell; PEG – polyethylene glycol; CEU – contrast-enhanced ultrasound
Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4+ stem cells into the ischaemic heart
Mechanism of PTH-mediated cardioprotection. PTH administration after MI induces mobilization of stem cells from the BM to the peripheral blood. These stem cells circulate to the damaged heart, where they are incorporated by interaction of intact myocardial SDF-1 and the homing receptor CXCR4. PTH inhibits DPP-IV activity and thereby prevents the degradation of intact SDF-1. Thus, an increased amount of SDF-1 improves homing of mobilized CXCR4+ cells. Altogether, PTH reduced cardiac remodelling after MI and enhanced cardiac function by attenuating the development of ischaemic cardiomyopathy.
Cardiac cell types derived from multipotent progenitors. Differentiated cardiac cell types are marked by indicated genes (green). Recently, several factors have been defined as master regulators for cardiomyogenesis (red). The combination of Tbx5, Gata4, and Baf60c induces direct differentiation of mesodermal cells into ectopic beating myocytes, bypassing the cardiac progenitor state.55 Tbx5, Gata4, and Mef2c together can also induce cardiomyocytes from fibroblasts.91 Factors for direct induction of other cardiac cell types are currently unknown (question marks).
Biphasic development of the ventricular conduction system.
The ventricular conduction system controls the propagation of electrical activity through the heart to coordinate cardiac contraction. To define the lineage relationship between cells of the murine ventricular conduction system and surrounding working myocytes, we used a retrospective clonal analysis to study the properties of clonally related cells. (A) Retrospective nlaacZ clonal analysis of the ventricular conduction system demonstrates two types of clusters. Mixed clusters composed of conductive and working myocytes reveal that both cell types develop from common progenitor cells, while unmixed clusters composed of either conductive or working myocytes show that proliferation continues after lineage restrictions. (B) The relative small size of unmixed conductive clusters in comparison to mixed clusters or to unmixed contractile clusters shows that proliferation follows cell lineage restriction and that proliferation is more limited for conductive cells than for working cardiomyocytes, respectively. This established that the ventricular conduction system developed by a biphasic mode of development: differentiation from a common myogenic progenitor followed by limited proliferation of conductive myocytes.