SinoXivMitochondrial donation recapitulates physiological niche signalling to promote metabolic plasticity, expansion, and engraftment of hematopoietic progenitors
Abstract
Umbilical cord blood (UCB) transplantation effectively treats pediatric hematologic disorders, but insufficient multipotent progenitors delay immune reconstitution, severely restricting its clinical application in adults. Here, we established that mesenchymal stromal cells’ mitochondrial donation to UCB hematopoietic stem cells accelerates immune recovery, identifying mitochondrial donation as a constitutive physiological regulator. Using Prx1CreER-driven mitochondrial reporters, we demonstrate that stromal niche cells spontaneously transfer mitochondria to hematopoietic progenitors in vivo. Mechanistically, this transfer reinforces glycolytic quiescence in stem cells while activating oxidative phosphorylation in multipotent progenitors. This compartment-specific remodelling drives >100-fold multipotent progenitor enrichment and 40-fold early progenitor expansion. Crucially, the respiratory competence of transferred mitochondria is essential, since respiration-deficient mitochondria fail to support this reprogramming. In competitive xenografts, mitochondrial-enhanced UCB achieves 3-fold greater engraftment and accelerated T-cell reconstitution. These findings reveal that mitochondrial integrity orchestrates metabolic programs to balance stem cell preservation with therapeutic amplification, offering a strategy to optimize UCB transplantation.
Citation Information
@article{marounkhoury2026,
title={Mitochondrial donation recapitulates physiological niche signalling to promote metabolic plasticity, expansion, and engraftment of hematopoietic progenitors},
author={Maroun Khoury and Radmila Velarde and Angela Court and Gino Nardocci and André Weber and Pierre Henry and Rocio Lorca and Nicolás Georges-Calderón and Diego Irribarra and Elisa Balboa8 and Rodrigo Herrera-Molina and Sarah Ezquerra and Sebastian Illanes and Fernando Figueroa},
journal={Nature Portfolio},
year={2026},
doi={https://doi.org/10.21203/rs.3.rs-8844855/v1}
}
