Mitochondrial transfer mediates endothelial cell engraftment through mitophagy

Nature. 2024 May;629(8012):660-668. doi: 10.1038/s41586-024-07340-0. Epub 2024 May 1.

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.

MeSH terms

  • Animals
  • Autophagosomes / metabolism
  • Cell- and Tissue-Based Therapy* / methods
  • Endothelial Cells* / cytology
  • Endothelial Cells* / metabolism
  • Endothelial Cells* / transplantation
  • Energy Metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Ischemia* / metabolism
  • Ischemia* / therapy
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Nude
  • Mitochondria* / metabolism
  • Mitochondria* / transplantation
  • Mitophagy*
  • Protein Kinases / deficiency
  • Protein Kinases / metabolism
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Ubiquitin-Protein Ligases