Role of Cell Communication and Transient Nanotubules Between Cardiomyocytes and Mesenchymal Stem Cells for Myocardial Repair

Jessica Clothier

Introduction. Coronary Artery Disease is the number one leading cause of death in the US, and is responsible for 1 in 6 deaths.1 There is a quick system for reperfusion during a myocardial infarction, but there is not yet a solution to the permanent damage of the myocardium. Those who survive an MI are at risk of papillary muscle rupture, wall rupture, or ventricular septal defect.2 Most will later suffer from heart failure. Researchers see the potential of mesenchymal stem cells (MSCs) for this gap and study the communication that occurs between injured cardiomyocytes (CMs) and injected MSCs. Methods. Each study induced ischemia in CMs by exposure to ROS3, deprivation of serum and glucose4, treatment with LPS5, or exposure to hypoxia.4,6 Apoptosis was confirmed in CMs, then they were co-cultured with MSCs. Cell fusion and transient nanotubule (TNT) formation were observed, intercellular exchanges were monitored with flow cytometry and microscopy, and paracrine levels and mitochondrial membrane potentials were monitored.3-6 Results. H2O2 treatment led to significantly higher fusion rates, and the correlation between cell fusion and completion of apoptosis is inverse. Apoptosis was also reduced by culturing CMs and MSCs in separate chambers, which suggested that apoptosis can decrease by paracrine factors alone. The percentage of apoptotic cells, however, is further reduced by co-culturing, displaying that cell fusion further reduces apoptosis.3 Co-cultured MSCs had increased secretion levels of VEGF, HGF, SDF-1a, MCP-3, Interleukin 6, and Growth Regulated Oncogene alpha, as well as a maximized capacity for angiogenesis and recruiting bone marrow cells.6 Co-cultured CMs additionally exhibited a significantly higher mitochondrial membrane potential compared with the CMs exposed to the ischemic treatment only. When LatA was introduced in some samples, CMs were not rescued from apoptosis.4 MSCs are more likely to initiate TNT formation than CMs, but the CM membrane composes the TNT. Mitochondrial transfer from MSC to CM was observed between 16 CM-MSC pairs.5 Conclusions. Damaged CMs have a higher fusion rate that does not occur on any significant level in uninjured cells.3 Through crosstalk with TNTs, injured CMs induce an increase in the level of paracrine factors secreted from MSCs.6 The anti-apoptotic ability of MSCs can be attributed to mitochondrial recovery of injured CMs, which is mediated by TNTs. Direct co-culture with MSCs significantly restores mitochondrial function of an impaired CM.4 This unidirectional mitochondrial transfer from MSC to CM may be triggered by CM damage or an apoptotic signal.5

  1. Dai X, Wiernek S, Evans JP, & Runge MS. Genetics of coronary artery disease and myocardial infarction. World Journal of Cardiology. 2016; 8(1), 1–23.
  2. Tong, C., MD-PhD FACC. (2017, May 16). Ischemic Heart Disease: Focus on Myocardial Infarction. Lecture presented in TX – Bryan.
  3. Yang W-J, Li S-H, Weisel RD, Liu S-M, Li R-K. Cell fusion contributes to the rescue of apoptotic cardiomyocytes by bone marrow cells. Journal of Cellular and Molecular Medicine. 2012;16(12):3085-3095. doi:10.1111/j.1582-4934.2012.01600.x.
  4. Han H, Hu J, Yan Q, et al. Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitrosimulated ischemia/reperfusion model. Molecular Medicine Reports. 2016;13(2):1517-1524. doi:10.3892/mmr.2015.4726.
  5. Yang H, Borg TK, Ma Z, Xu M, Wetzel G, Saraf LV, Markwald R, Runyan RB, Gao BZ. Biochip-based study of unidirectional mitochondrial transfer from stem cells to myocytes via tunneling nanotubes. Biofabrication. 2016;8(1):015012. doi: 10.1088/1758-5090/8/1/015012.
  6. Figeac F, Lesault P-F, Le Coz O, Damy T, Souktani R, Trébeau C, Schmitt A, Ribot J, Mounier R, Guguin A, Manier C, Surenaud M, Hittinger L, Dubois-Randé J-L and Rodriguez A.-M. Nanotubular Crosstalk with Distressed Cardiomyocytes Stimulates the Paracrine Repair Function of Mesenchymal Stem Cells. Stem Cells, 2014; 32: 216–230. doi:10.1002/stem.1560