SummaryMesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.

This study aimed to investigate postinfarct left ventricular (LV) fiber structural alterations by ex vivo diffusion tensor imaging (DTI) in a porcine heart model. In vivo cardiac MR imaging was first performed to measure ventricular function in six adult pigs with septal infarction near apex induced by the LAD ligation 13 weeks earlier. Hearts were then excised from the infarct pigs (n ‫؍‬ 6) and six intact controls (n ‫؍‬ 6) and fixed in formalin. High-resolution DTI was employed to examine changes in fractional anisotropy (FA), apparent diffusion coefficient (ADC), and transmural helix angle distribution in the infarct, adjacent and remote regions as compared to the sham regions in the controls. FA values were found to decrease in the infarct and differ between the adjacent and remote regions. ADC increase in the infarct region was substantial, while changes in the adjacent and remote regions were insignificant. Structurally, the doublehelix myocardial structure shifted toward more left-handed around the infarcted myocardium. Accordingly, the histological analysis revealed clear fiber structural degradation in the adjacent region. These findings confirmed the subtle alterations in the myocardial fiber quality and structure not only in the in- Key words: myocardium infarction; borderzone; diffusion tensor imaging; fiber architecture Both structural and functional assessments are important in our understanding of myocardial contraction and relaxation in normal and pathologic states (1,2). It has been long known that left ventricular (LV) myocardial microstructure or fiber structure plays a critical role in determining mechanical properties, such as ventricular torsion, strain, and stress (3,4). Owing to the recent advances in cardiac MR and ultrasound imaging, there is an increasing interest in investigating LV by directly associating the LV myocardial fiber geometry to the complex spatial-temporal sequence of electrical activation and mechanical contraction/relaxation in beating hearts (1,2,5). LV is known to electrically activate first at the exits of Purkinje system, close to apical endocardium. The electrical activation then propagates from apex to base via depolarization and repolarization in both septum and free wall (1,6). This is accompanied by successive mechanical shortenings and intracavitary blood flow along the parallel apex-to-base direction, although highly transient and localized myocardial deformations exist.In infarcted myocardium, remodeling involves both structural and functional changes. Such changes have been found to occur in both infarcted myocardium and adjacent and remote myocardium (7-11). The effects of myocardial infarction (MI) on LV function have been investigated in numerous studies. In recent years, cardiac MR (CMR) imaging has become the accepted reference standard to assess LV function since CMR methods are both accurate and highly reproducible (12). These CMR techniques can be used to detect, localize, and quantify both MI and LV functions. Patten et al. (13) found that hearts...

Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) can protect cardiomyocytes against anthracycline-induced cardiomyopathy (AIC) through paracrine effects. Nonetheless the paracrine effects of human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) on AIC are poorly understood. In vitro studies reveal that doxorubicin (Dox)-induced reactive oxidative stress (ROS) generation and cell apoptosis in neonatal rat cardiomyocytes (NRCMs) are significantly reduced when treated with conditioned medium harvested from BM-MSCs (BM-MSCs-CdM) or iPSC-MSCs (iPSC-MSCs-CdM). Compared with BM-MSCs-CdM, NRCMs treated with iPSC-MSCs-CdM exhibit significantly less ROS and cell apoptosis in a dose-dependent manner. Transplantation of BM-MSCs-CdM or iPSC-MSCs-CdM into mice with AIC remarkably attenuated left ventricular (LV) dysfunction and dilatation. Compared with BM-MSCs-CdM, iPSC-MSCs-CdM treatment showed better alleviation of heart failure, less cardiomyocyte apoptosis and fibrosis. Analysis of common and distinct cytokines revealed that macrophage migration inhibitory factor (MIF) and growth differentiation factor-15 (GDF-15) were uniquely overpresented in iPSC-MSC-CdM. Immunodepletion of MIF and GDF-15 in iPSC-MSCs-CdM dramatically decreased cardioprotection. Injection of GDF-15/MIF cytokines could partially reverse Dox-induced heart dysfunction. We suggest that the potent paracrine effects of iPSC-MSCs provide novel “cell-free” therapeutic cardioprotection against AIC, and that MIF and GDF-15 in iPSC-MSCs-CdM are critical for these enhanced cardioprotective effects.