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

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

doi:10.1038/s41536-021-00167-7

Cited by 21 publications

(17 citation statements)

References 56 publications

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“…The first clinical trial of mitochondrial augmentation therapy (MAT) was opened ( ClinicalTrials.gov Identifier: NCT03384420 ) and offered patients and families new hope. In this trial, G-CSF mobilized HSCs of PS patients are subjected to ex-vivo mitochondrial augmentation with maternal mitochondria carrying normal mtDNA [ 9 – 12 ]. These autologous HSCs containing normal maternal mtDNA are reinfused in the patient.…”

Section: Hematological Coursementioning

confidence: 99%

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Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure

Yoshimi

Ishikawa

Niemeyer

et al. 2022

Orphanet J Rare Dis

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Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1–3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.

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Section: Hematological Coursementioning

confidence: 99%

“…The majority of patients die before 6 years of age [ 3 – 5 , 7 , 8 ]. Recently, increasing attention is being paid to PS due to development of novel therapies for PMDs, which can potentially be applied in children with this rare disease [ 9 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure

Yoshimi

Ishikawa

Niemeyer

et al. 2022

Orphanet J Rare Dis

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“…Because of this, mitochondrial replacement or supplementation in cells is being proposed as novel therapeutic approach of mitochondrial diseases. A recent study shows that mitochondrial augmentation in human CD34+ cells from healthy donors or patients with mitochondrial DNA disorder can prove beneficial ( 68 ). The group described a method of ex vivo transfer of HSPC with normal exogenous mitochondria, that they termed mitochondrial augmentation therapy (MAT).…”

Section: Other Mitochondrial Abnormalities Linked To Inherited Bmfmentioning

confidence: 99%

“…They show that MAT can improve mitochondrial content and oxygen consumption of healthy and diseased HSPCs. Importantly, they used xenotransplant in immunodeficient NSGS mice to show that MAT confers HSPCs from a patient with an mtDNA disorder superior human engraftment ( 68 ).…”

Section: Other Mitochondrial Abnormalities Linked To Inherited Bmfmentioning

confidence: 99%

Acquired and hereditary bone marrow failure: A mitochondrial perspective

Nasr

Filippi

2022

Front. Oncol.

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The disorders known as bone marrow failure syndromes (BMFS) are life-threatening disorders characterized by absence of one or more hematopoietic lineages in the peripheral blood. Myelodysplastic syndromes (MDS) are now considered BMF disorders with associated cellular dysplasia. BMFs and MDS are caused by decreased fitness of hematopoietic stem cells (HSC) and poor hematopoiesis. BMF and MDS can occur de novo or secondary to hematopoietic stress, including following bone marrow transplantation or myeloablative therapy. De novo BMF and MDS are usually associated with specific genetic mutations. Genes that are commonly mutated in BMF/MDS are in DNA repair pathways, epigenetic regulators, heme synthesis. Despite known and common gene mutations, BMF and MDS are very heterogenous in nature and non-genetic factors contribute to disease phenotype. Inflammation is commonly found in BMF and MDS, and contribute to ineffective hematopoiesis. Another common feature of BMF and MDS, albeit less known, is abnormal mitochondrial functions. Mitochondria are the power house of the cells. Beyond energy producing machinery, mitochondrial communicate with the rest of the cells via triggering stress signaling pathways and by releasing numerous metabolite intermediates. As a result, mitochondria play significant roles in chromatin regulation and innate immune signaling pathways. The main goal of this review is to investigate BMF processes, with a focus mitochondria-mediated signaling in acquired and inherited BMF.

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“…Alternatively, it may be possible to isolate T cells from RA synovial fluid and modify them ex vivo with exogenous healthy mitochondria to inhibit proinflammatory cytokine production, followed by reinfusion into the joint. A recent study showed that exogenous mitochondria can enhance engraftment of bone marrow, suggesting that ex vivo mitochondria transfer could be harnessed in multiple therapeutic contexts [ 21 ]. At least three startup biotech companies (Minovia, Mitrix, and Cellvie) are attempting to develop the use of exogenous mitochondria for therapeutic purposes.…”

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confidence: 99%

Mitochondria Transfer to CD4+ T Cells May Alleviate Rheumatoid Arthritis by Suppressing Pro-Inflammatory Cytokine Production

Giwa

Brestoff

2022

Immunometabolism

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CD4 + T cells contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). These cells infiltrate the joints of RA patients and produce cytokines, including Tumor necrosis factor (TNF)-α, that drive joint inflammation and bone destruction. Although biologic therapeutics targeting T cells and TNF-α have benefited patients suffering from RA, some patients are refractory to these therapies, develop antibodies that neutralize these biologics, or develop undesirable side effects. Recent studies indicate that CD4 + T cell cytokine production is regulated in part by specific metabolic modules, suggesting that immunometabolic pathways could represent a novel therapeutic strategy for T cell-mediated diseases such as RA. Wu et al. (2021) demonstrate that mitochondrial function is impaired in CD4 + T cells from RA patients, leading to reduced levels of various citric acid cycle metabolites (e.g., aspartate) that regulate TNF-α production. Treatment of RA-associated T cells with purified mitochondria was sufficient to restore these metabolic defects, limit production of numerous pro-inflammatory cytokines such as TNF-α and IL-17A, and reduce the development of RA-like disease in a humanized mouse model. These data suggest that T cells can be metabolically “re-engineered” ex vivo with exogenous mitochondria and that this mitochondria transfer approach confers anti-inflammatory properties that may reduce disease severity in RA and possibly other rheumatologic diseases. Increasing our understanding of how intercellular mitochondria transfer occurs may identify novel biological pathways that can be targeted therapeutically or harnessed to support cell engineering.

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

Cited by 21 publications

References 56 publications

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure

Acquired and hereditary bone marrow failure: A mitochondrial perspective

Mitochondria Transfer to CD4+ T Cells May Alleviate Rheumatoid Arthritis by Suppressing Pro-Inflammatory Cytokine Production

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