Journal
STEM CELL REPORTS
Volume 7, Issue 4, Pages 749-763Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2016.08.009
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Funding
- HKU Small Project Funding [201409176221, 201007176100]
- Theme-based Research Scheme [T12-705/11]
- Science and Technology Foundation of Guangdong Province [2015B020225001]
- HKU State Key Laboratory of Pharmaceutical Biotechnology
- National Natural Science Foundation of China [31270967, 31571407]
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Mesenchymal 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 TNF alpha IP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-alpha)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-alpha/NF-kappa B/ TNF alpha IP2 signaling pathway. Inhibition of TNFaIP2 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-alpha-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.
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