Mitochondrial transfer mediates endothelial cell engraftment through mitophagy

Ruei-Zeng Lin, Gwang-Bum Im, Allen Chilun Luo, Yonglin Zhu, Xuechong Hong, Joseph Neumeyer, Hong-Wen Tang, Norbert Perrimon and Juan M. Melero-Martin ()
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Ruei-Zeng Lin: Boston Children’s Hospital
Gwang-Bum Im: Boston Children’s Hospital
Allen Chilun Luo: Boston Children’s Hospital
Yonglin Zhu: Boston Children’s Hospital
Xuechong Hong: Boston Children’s Hospital
Joseph Neumeyer: Boston Children’s Hospital
Hong-Wen Tang: Harvard Medical School
Norbert Perrimon: Harvard Medical School
Juan M. Melero-Martin: Boston Children’s Hospital

Nature, 2024, vol. 629, issue 8012, 660-668

Abstract: Abstract Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1–Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.

Date: 2024
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DOI: 10.1038/s41586-024-07340-0

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