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De-stressing Stem Cells May Improve Clinical Utility

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Review of “Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock” from Cell by Stuart P. Atkinson

Hematopoietic stem cell (HSC) harvesting and transplantation is an important strategy for the treatment of various blood disorders/diseases, but the relative rarity of the stem cells themselves can limit effectiveness [1]. Their number and function also deteriorate both during their collection from the bone marrow (BM) and in vitro manipulation but the development of in vitro conditions which best mimic the in vivo HSC niche environment may help to minimize this loss. One of the most important variables for HSC viability is oxygen concentration, as various studies have shown that ambient air oxygen concentrations in vitro may be deleterious for HSCs which normally reside in hypoxic niches in vivo. Now, researchers from the laboratory of Hal E. Broxmeyer (Indiana University School of Medicine, USA) have found that HSCs suffer from ‘‘extra-physiologic oxygen shock/stress (EPHOSS)” when harvested under ambient oxygen conditions. Furthermore, they demonstrate how treatment with the immunosuppressant drug cyclosporin A (CSA) can inhibit this stress, enhance the yield of collected HSCs, and increase transplantation efficacy [2].

Initial comparisons of mouse BM harvested under normoxia (21% O2) and hypoxia (3% O2) found that hypoxic treatment mediated a 5-fold increase in the number of Long Term (LT) self-renewing HSCs, and a decrease in harmful reactive oxygen species (ROS) and mitochondrial activity. The researchers also confirmed the positive effect of hypoxia on HSC collection from human cord blood. Excitingly, functional assessment of mouse BM HSCs by competitive transplantation found that “hypoxic HSCs” engrafted more efficiently in recipient mice and this was not due to enhanced homing or reduced apoptosis, overall suggesting that the stress response to non-physiological oxygen concentrations (EPHOSS) has a rapid and significant deleterious effect in HSCs.

Induction of the mitochondrial permeability transition pore (MPTP) is one key mechanism by which oxidative stress may mediate its deleterious effects to HSCs. MPTP induction can lead to mitochondrial swelling and uncoupled oxidative phosphorylation [3] leading to apoptosis and necrosis [4], although intermittent MPTP activation may also act to dysregulate stem cell function. To test this hypothesis, the study employed cyclosporin A (CSA) to antagonize MPTP induction through the inhibition of the associated CypD protein. Excitingly, cell harvesting under normoxic conditions in the presence of CSA resulted in a 4-fold recovery of LT-HSC numbers and enhanced engraftment levels as compared to normoxic HSC harvesting in the absence of CSA, specifically through the suppression of MPTP induction. This link was further strengthened through the assessment of mice with a deletion of the CypD gene in which the group observed increased LT-HSC recovery and decreased LT-HSC ROS levels after normoxic BM harvesting as compared to wild type mice.

While harvesting and further processing cells in a hypoxic environment within the clinic is generally unfeasible, even given the observed advantages, the application of CSA may represent an easy and attractive alternative. Indeed the authors note that CSA is already used in the clinic as an immunosuppressant and so may rapidly adapted into bone marrow harvesting techniques. Additionally, this paper also suggests that studies using other types of stem cells for transplantation may need to consider the effects of EPHOSS and oxygen concentration while preparing their cells in each model system. 

References

  1. Ballen KK, Gluckman E, and Broxmeyer HE Umbilical cord blood transplantation: the first 25 years and beyond. Blood 2013;122:491-498.
  2. Mantel CR, O'Leary HA, Chitteti BR, et al. Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell 2015;161:1553-1565.
  3. Halestrap AP and Davidson AM Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. The Biochemical journal 1990;268:153-160.
  4. Vaseva AV, Marchenko ND, Ji K, et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 2012;149:1536-1548.

Comments

I would like to ask where, how and in what dose Cyclosporin A was used. Intravenous to the host?

"CSA harvests (50 mg/ml) were used for BM collection and also injected intraperitoneally at 100 mg into mice 18–24 hr before BM harvest" - See the full text for all the information on the experiments - http://www.ncbi.nlm.nih.gov/pubmed/26073944.

I would like to know the link between mir210 and Hif-1a with p53-CypD-MPTP axis in your experiments. I also want to know that your main data or supplement did not include any experiments in which you have harvested & processed cells under hypoxia from cypD gene knockout mice. Isn't it worth to check?

Perhaps the original paper will be able to help you out with your question? If not, I'm sure that if you contact the authors, they may be able to help you!