title: Transcatheter based electromechanical mapping guided intramyocardial transplantation and in vivo tracking of human stem cell based three dimensional microtissues in the porcine heart.
abstract: Stem cells have been repeatedly suggested for cardiac regeneration after myocardial infarction (MI). However, the low retention rate of single cell suspensions limits the efficacy of current therapy concepts so far. Taking advantage of three dimensional (3D) cellular self-assembly prior to transplantation may be beneficial to overcome these limitations. In this pilot study we investigate the principal feasibility of intramyocardial delivery of in-vitro generated stem cell-based 3D microtissues (3D-MTs) in a porcine model. 3D-MTs were generated from iron-oxide (MPIO) labeled human adipose-tissue derived mesenchymal stem cells (ATMSCs) using a modified hanging-drop method. Nine pigs (33 ± 2 kg) comprising seven healthy ones and two with chronic MI in the left ventricle (LV) anterior wall were included. The pigs underwent intramyocardial transplantation of 16 × 10(3) 3D-MTs (1250 cells/MT; accounting for 2 × 10(7) single ATMSCs) into the anterior wall of the healthy pigs (n = 7)/the MI border zone of the infarcted (n = 2) of the LV using a 3D NOGA electromechanical mapping guided, transcatheter based approach. Clinical follow-up (FU) was performed for up to five weeks and in-vivo cell-tracking was performed using serial magnet resonance imaging (MRI). Thereafter, the hearts were harvested and assessed by PCR and immunohistochemistry. Intramyocardial transplantation of human ATMSC based 3D-MTs was successful in eight animals (88.8%) while one pig (without MI) died during the electromechanical mapping due to sudden cardiac-arrest. During FU, no arrhythmogenic, embolic or neurological events occurred in the treated pigs. Serial MRI confirmed the intramyocardial presence of the 3D-MTs by detection of the intracellular iron-oxide MPIOs during FU. Intramyocardial retention of 3D-MTs was confirmed by PCR analysis and was further verified on histology and immunohistochemical analysis. The 3D-MTs appeared to be viable, integrated and showed an intact micro architecture. We demonstrate the principal feasibility and safety of intramyocardial transplantation of in-vitro generated stem cell-based 3D-MTs. Multimodal cell-tracking strategies comprising advanced imaging and in-vitro tools allow for in-vivo monitoring and post-mortem analysis of transplanted 3D-MTs. The concept of 3D cellular self-assembly represents a promising application format as a next generation technology for cell-based myocardial regeneration.
authors: Swiss Centre for Regenerative Medicine, University of Zurich, Zurich, Switzerland.
authors: Maximilian Y
authors: MY
authors: Emmert
authors: Petra
authors: P
authors: Wolint
authors: Sebastian
authors: S
authors: Winklhofer
authors: Paul
authors: P
authors: Stolzmann
authors: Nikola
authors: N
authors: Cesarovic
authors: Thea
authors: T
authors: Fleischmann
authors: Thi D L
authors: TD
authors: Nguyen
authors: Thomas
authors: T
authors: Frauenfelder
authors: Roland
authors: R
authors: Böni
authors: Jacques
authors: J
authors: Scherman
authors: Dominique
authors: D
authors: Bettex
authors: Jürg
authors: J
authors: Grünenfelder
authors: Ruth
authors: R
authors: Schwartlander
authors: Viola
authors: V
authors: Vogel
authors: Mariann
authors: M
authors: Gyöngyösi
authors: Hatem
authors: H
authors: Alkadhi
authors: Volkmar
authors: V
authors: Falk
authors: Simon P
authors: SP
authors: Hoerstrup
mesh_terms: D000818:Animals; D005260:Female; D006333:Heart Failure / Q000628:therapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009203:Myocardial Infarction / Q000628:therapy; D009206:Myocardium / Q000378:metabolism; D044968:Regenerative Medicine; D013552:Swine