UCSF

Cardiac cell therapy for myocardial infarction has been extensively studied due to its regenerative potential. However, the success of cardiac cell therapy is greatly limited by delivery efficiency, cell fate after delivery, and possible proarrhythmia associated with some cell types. To successfully improve efficiency of cardiac cell therapy, we herein proposed a new bispecific antibody (BiAb) targeting technology to efficiently deliver therapeutical cells to myocardial injury by chemically linking monoclonal antibody specifics to myocardial injury and another monoclonal antibody binding to the therapeutical cells. To reach this goal, in this work, we first optimized the method to arm BiAb to human hematopoietic stem cells (hHSCs) and consequently verified that the BiAb armed hHSCs could be successfully and efficiently delivered to injured myocardium. By comparing and contrasting the BiAb targeting method with more conventional systematical administration and direct injection into damaged myocardium;, we investigated the beneficial effect of hHSCs in improving/preserving cardiac function and reducing the size of infarction and explored the angiogenic mechanism of hHSCs in myocardial infarction. We also studied whether or not hHSCs are proarrhythmic by comparing the ventricular tachycardia inducibility, effective refractory period and conduction velocity between treatment and a control group and a new analytic method of electrophysiological data was proposed and compared with traditional approaches based on time series analysis.

Overall results in this work demonstrated that BiAb targeting is significantly better than systematical administration and comparable, if not better, to direction injection in terms of preserving cardiac function, reducing myocardial infarction size, and promoting angiogenesis in myocardial infarction. Human HSCs are not proarrhythmic and hHSCs targeted by BiAb showed improved electrophysiological properties than control group. Therefore we concluded that BiAb targeting is an effective and efficiently delivery method and it further leads the therapeutical cells to a more favorable milieu to help the cell survival; hHSCs preserved cardiac function with the aid of BiAb through angiogenesis.