npj Regenerative Medicine (Sep 2021)

Mitochondrial augmentation of CD34+ cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit

  • Elad Jacoby,
  • Moriya Ben Yakir-Blumkin,
  • Shiri Blumenfeld-Kan,
  • Yehuda Brody,
  • Amilia Meir,
  • Naomi Melamed-Book,
  • Tina Napso,
  • Gat Pozner,
  • Esraa Saadi,
  • Ayelet Shabtay-Orbach,
  • Natalie Yivgi-Ohana,
  • Noa Sher,
  • Amos Toren

DOI
https://doi.org/10.1038/s41536-021-00167-7
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 12

Abstract

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Abstract Mitochondria are cellular organelles critical for numerous cellular processes and harboring their own circular mitochondrial DNA (mtDNA). Most mtDNA associated disorders (either deletions, mutations, or depletion) lead to multisystemic disease, often severe at a young age, with no disease-modifying therapies. Mitochondria have a capacity to enter eukaryotic cells and to be transported between cells. We describe a method of ex vivo augmentation of hematopoietic stem and progenitor cells (HSPCs) with normal exogenous mitochondria, termed mitochondrial augmentation therapy (MAT). Here, we show that MAT is feasible and dose dependent, and improves mitochondrial content and oxygen consumption of healthy and diseased HSPCs. Ex vivo mitochondrial augmentation of HSPCs from a patient with a mtDNA disorder leads to superior human engraftment in a non-conditioned NSGS mouse model. Using a syngeneic mouse model of accumulating mitochondrial dysfunction (Polg), we show durable engraftment in non-conditioned animals, with in vivo transfer of mitochondria to recipient hematopoietic cells. Taken together, this study supports MAT as a potential disease-modifying therapy for mtDNA disorders.