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

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.

SUBMITTER: Jacoby E

PROVIDER: S-EPMC8463667 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Mitochondrial augmentation of CD34<sup>+</sup> cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit.

Jacoby Elad E Ben Yakir-Blumkin Moriya M Blumenfeld-Kan Shiri S Brody Yehuda Y Meir Amilia A Melamed-Book Naomi N Napso Tina T Pozner Gat G Saadi Esraa E Shabtay-Orbach Ayelet A Yivgi-Ohana Natalie N Sher Noa N Toren Amos A

NPJ Regenerative medicine 20210924 1

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) w ...[more]

PMID: 34561447

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Project description:Hematopoietic stem cells can be mobilized from healthy donors using single-agent plerixafor without granulocyte colony-stimulating factor and, following allogeneic transplantation, can result in sustained donor-derived hematopoiesis. However, when a single dose of plerixafor is administered at a conventional 240 μg/kg dose, approximately one-third of donors will fail to mobilize the minimally acceptable dose of CD34+ cells needed for allogeneic transplantation. We conducted an open-label, randomized trial to assess the safety and activity of high-dose (480 μg/kg) plerixafor in CD34+ cell mobilization in healthy donors. Subjects were randomly assigned to receive either a high dose or a conventional dose (240 μg/kg) of plerixafor, given as a single subcutaneous injection, in a two-sequence, two-period, crossover design. Each treatment period was separated by a 2-week minimum washout period. The primary endpoint was the peak CD34+ count in the blood, with secondary endpoints of CD34+ cell area under the curve (AUC), CD34+ count at 24 hours, and time to peak CD34+ following the administration of plerixafor. We randomized 23 subjects to the two treatment sequences and 20 subjects received both doses of plerixafor. Peak CD34+ count in the blood was significantly increased (mean 32.2 versus 27.8 cells/μL, P=0.0009) and CD34+ cell AUC over 24 hours was significantly increased (mean 553 versus 446 h cells/μL, P<0.0001) following the administration of the 480 μg/kg dose of plerixafor compared with the 240 μg/kg dose. Remarkably, of seven subjects who mobilized poorly (peak CD34+ ≤20 cells/μL) after the 240 μg/kg dose of plerixafor, six achieved higher peak CD34+ cell numbers and all achieved higher CD34+ AUC over 24 hours after the 480 μg/kg dose. No grade 3 or worse drug-related adverse events were observed. This study establishes that high-dose plerixafor can be safely administered in healthy donors and mobilizes greater numbers of CD34+ cells than conventional-dose plerixafor, which may improve CD34+ graft yields and reduce the number of apheresis procedures needed to collect sufficient stem cells for allogeneic transplantation. (ClinicalTrials.gov, identifier: NCT00322127).

Dataset Information

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

Publications

Mitochondrial augmentation of CD34<sup>+</sup> cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit.

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Dataset Information

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

Publications

Mitochondrial augmentation of CD34<sup>+</sup> cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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