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Creating Safer Stem Cell Therapies with Naked Mole Rat iPSCs!

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Review of “Tumour resistance in induced pluripotent stem cells derived from naked mole-rats” from Nature Communications by Stuart P. Atkinson

The naked mole rat thrives in harsh environments, has low metabolic and respiratory rates, and most interestingly of all, is resistant to cancer [1, 2]. This has led scientists to study these extraordinary animals in the hopes of revealing the intrinsic anti-cancer mechanisms that they possess. 

Researchers from the laboratories of Hideyuki Okano (Keio University School of Medicine, Tokyo, Japan) and Kyoko Miura (Hokkaido University, Japan) recently sought to generate induced pluripotent stem cells (iPSCs) from the skin of the naked mole rat. They undertook this task due to the many parallels of iPSC reprograming and cancer development [3, 4], which is one of the reasons we have concerns regarding tumorigenicity in cell therapies using transplanted iPSC-derived cells. 

Their new study, published in Nature Communications, aimed to generate and study naturally cancer-resistant naked mole rat iPSCs in the hope of uncovering strategies to produce safer stem cell therapies [5].

The generation of naked mole rat iPSCs via the retroviral transduction of the Oct4, Sox2, Klf4, and Myc (OSKM) reprogramming factors in naked mole rat skin fibroblasts led to the production of stem-like cells with multiple pluripotent characteristics within 2-3 weeks. However, while human and mouse iPSCs generated in a similar manner formed teratocarcinomas following injection into the testes in an immunodeficient mouse model, naked mole rat iPSCs engrafted in the testis without forming tumors.

Further investigations demonstrated that the activation of the tumour-suppressor alternative reading frame (ARF), and the presence of a disrupting mutation in the tumor promoting ES cell-expressed Ras (ERAS) oncogene mediated the anti-tumorigenic capacity of naked mole rat iPSCs. Interestingly, overexpression of Arf in mouse iPSCs (normally repressed) reduced tumorigenic capacity, suggesting that this modification may allow for the formation of “safer” iPSCs.

Further experiments with will hopefully ascertain whether stable knockdown of ARF or the introduction of mutations in the ERAS gene in human iPSCs will generate safer iPSCs which retain the ability to differentiate into therapeutically relevant cell types. Can iPSC generation in other animal species with desirable qualities lead to the creation of even safer stem cell therapies? Stay tuned to the Stem Cells Portal to find out!

References

  1. Buffenstein R Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 2008;178:439-445.
  2. Edrey YH, Hanes M, Pinto M, et al. Successful aging and sustained good health in the naked mole rat: a long-lived mammalian model for biogerontology and biomedical research. ILAR J 2011;52:41-53.
  3. Suva ML, Riggi N, and Bernstein BE Epigenetic reprogramming in cancer. Science 2013;339:1567-1570.
  4. Folmes CD, Nelson TJ, Martinez-Fernandez A, et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 2011;14:264-271.
  5. Miyawaki S, Kawamura Y, Oiwa Y, et al. Tumour resistance in induced pluripotent stem cells derived from naked mole-rats. Nat Commun 2016;7:11471.