Luping Zhang1, Xiaotong Li2, Xiaolong Yu3, Yuquan Li2, Aijun Sun2, Chao Huang2, Feng Xu2, Jinping Guo2, Yao Sun4, Xi Zhang5, Xiangqun Yang6, Chuansen Zhang7. 1. Department of Anatomy, Second Military Medical University, Shanghai, China; Department of Anatomy, Binzhou Medical University, Binzhou, China. 2. Department of Anatomy, Second Military Medical University, Shanghai, China. 3. Department of Anatomy, Second Military Medical University, Shanghai, China; The Affiliated Hospital of North China University of Science and Technology, Baoding, China. 4. The Affiliated Hospital of North China University of Science and Technology, Baoding, China. 5. Department of Anatomy, Second Military Medical University, Shanghai, China. Electronic address: zhangxicyl1126@163.com. 6. Department of Anatomy, Second Military Medical University, Shanghai, China. Electronic address: 13671622756@126.com. 7. Department of Anatomy, Second Military Medical University, Shanghai, China. Electronic address: chuansenzhang@126.com.
Abstract
AIMS: Transplantation of a tissue engineered cardiac pacemaker (TECP) may represent a novel therapy for cardiac sinus node dysfunction. We previously reported that cardiac progenitor cells (CPCs) derived from embryonic heart tubes could differentiate into cardiac pacemaking cells after endothelin-1 treatment. We aimed to examine the feasibility of TECP fabricated from CPCs-derived pacemaking cells and vascularization of TECP fabricated from CPCs-derived pacemaking cells and endothelial progenitor cells (EPCs) in vitro and in vivo implantation. MAIN METHODS: TECP created using CPCs-derived pacemaking cells and vTECP created by mixing CPCs and EPCs in vitro were implanted into rat hearts. Sinus node damaged was induced by formaldehyde insult. KEY RESULTS: Spontaneous beating tissues, namely TECP, were obtained after seeding CPCs-derived pacemaking cells into Matrigel. ECG and epicardial multielectrode array (MEA) measurements confirmed implanted TECP have electrical activity. TECP implantation promoted individual survival in sinus node damage models (15/22 animals lived versus 0/17 control). vTECP fabricated by mixing the both EPCs and CPCs-derived pacemaking cells with Matrigel in equal proportions optimally formed pre-vascularization in vitro. The implantation of vTECP enhanced electrical activity in vivo, which may correlate with increased vascularization. PI3K-Akt-VEGF/VEGFR signaling was involved with vascular ingrowth in vTECP. SIGNIFICANCE: Our data supports the therapeutic potential of TECP fabricated with the CPCs-derived pacemaking cells for sinus node dysfunction. Vascularization by the addition of EPCs is an important factor to sustain viability of the TECP in vivo.
AIMS: Transplantation of a tissue engineered cardiac pacemaker (TECP) may represent a novel therapy for cardiac sinus node dysfunction. We previously reported that cardiac progenitor cells (CPCs) derived from embryonic heart tubes could differentiate into cardiac pacemaking cells after endothelin-1 treatment. We aimed to examine the feasibility of TECP fabricated from CPCs-derived pacemaking cells and vascularization of TECP fabricated from CPCs-derived pacemaking cells and endothelial progenitor cells (EPCs) in vitro and in vivo implantation. MAIN METHODS: TECP created using CPCs-derived pacemaking cells and vTECP created by mixing CPCs and EPCs in vitro were implanted into rat hearts. Sinus node damaged was induced by formaldehyde insult. KEY RESULTS: Spontaneous beating tissues, namely TECP, were obtained after seeding CPCs-derived pacemaking cells into Matrigel. ECG and epicardial multielectrode array (MEA) measurements confirmed implanted TECP have electrical activity. TECP implantation promoted individual survival in sinus node damage models (15/22 animals lived versus 0/17 control). vTECP fabricated by mixing the both EPCs and CPCs-derived pacemaking cells with Matrigel in equal proportions optimally formed pre-vascularization in vitro. The implantation of vTECP enhanced electrical activity in vivo, which may correlate with increased vascularization. PI3K-Akt-VEGF/VEGFR signaling was involved with vascular ingrowth in vTECP. SIGNIFICANCE: Our data supports the therapeutic potential of TECP fabricated with the CPCs-derived pacemaking cells for sinus node dysfunction. Vascularization by the addition of EPCs is an important factor to sustain viability of the TECP in vivo.