ipSCs: the regenerative medicine of the future

A promising therapy to combat the biological effects of aging comes from the use of stem cells. In this article, we will talk about the latest advances on tissue regeneration via stem cells and discuss on the possibilities of such developments for the treatment of aging-related diseases.

Embryonic stem cell differentiation process and reversion by dedifferentiation (arrow right). Credit: Illustration from Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013

For a few years, stem cell therapy has become the “fashion” among scientist and the general public alike, specially for the enormous clinical potential it supposses. With the initial steps of the technology, a number of ethical issues came to light, specially those regarding the use of embryonic stem cells. But let’s go back a minute here to explain what a stem cell is, even when a quick look on wikipedia would already answer the question, an easy explanation would be that stem cells are undifferentiated cells with the potential of turning into whichever cell type of the organism necessary, from this it is understandable why in principle stem cells came from embryos because if you remember your basic biology class, from a single cell egg a whole individual is produced, with different organs, tissues etc. Amazing right?

About 10 years ago, the nobel-prize laureate Yamanake and his team found that one could transform fibroblasts (adult cells, with a defined identity) back into pluripotent stem cells (ipSC) by the use of 4 transcription factors, and with that the whole ethical issue of using embryonic stem cells became a thing of the past (to some extent). Moreover, since they can be derived from the patient herself, they reduce the likelihood of rejection.

Like all such advances, they don’t come for free. Among the major problems regarding the use of in vitro derived ipSCs are the administration route and their stability upon tissue injection. It is really important to assess the minimum number of undifferentiated ipSCs that could develop into a teratoma, since residual undifferentiated cells might remain after differentiation into specific cell types and produce tumors. An approach under development is set out to induce differentiation of ipSCs already after transplantation in the patient, via genetic drug-activable factors that would induce expression of the transcription factors needed for differentiation. However, this technique has only been tested in rodents, and we will have to wait a while till we see the first trials in humans.

An important point is whether this technique would be at all successful in aged organisms. Since aging at the cellular level implicates a decline of stem cell production and a stable arrest of cell cycle together with the accumulation of genetic abnormalities, it would be logical to expect that cell reprogramming would not be so efficient in aged cells, and even though there are reports on this direction, other researches have found no issues to reprogramming potential in senescent cells from old people, including even centenarians (even when it could be posed that centenarians have maintained better cell integrity, allowing them to reach this extended life span). The potential for rejuvenation derived from reprogramming could be observed in ipSCs derived even from centenarians, where telomere length (a marker of cellular aging) was increased, as was mitochondrial function, while there was an observable loss of cellular senescence markers.

Credit: Häggström, Mikael. “Medical gallery of Mikael Häggström 2014”. Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762

Another possibility to revert cellular senescence could be targeted directly to know molecular pathways involved in cellular aging. For instance, inhibition of the DOT1-like histone H3K79methyltransferase (DOT1L) in progeroid mice extended their lifespan and conduced to a rejuvenated phenotype. Moreover, inhibition of the nuclearfactor kappa-light-chain-enhancer of activated B cells (NFk-B) significantly increased the reprogramming efficiency of fibroblasts from aged patients. Therefore, interventions directed towards modulation of the NFk-B pathway might stand as a potential therapy target to impede progression of aging-related diseases.

In conclusion, ipSCs purport a great therapeutical potential in the treatment of aging-related diseases. However, until this technique becomes a standard of care, more research is needed to make sure the benefit/risk ratio becomes acceptable, by limiting the likelihood for tumorigenic events derived from undifferentiated ipSCs and improving on the delivery systems, to increase efficiency and limit the chances of rejection, by aiming towards autologous transplantation methods.

 

Pareja-Galeano H, et al. iPSCs-based anti-aging therapies: Recent discoveries and future challenges. Ageing Res Rev. 2016 May;27:37-41. doi: 10.1016/j.arr.2016.02.007. Epub 2016 Feb 26.

Further reading:

Agarwal, S., Loh, Y.H., McLoughlin, E.M., Huang, J., Park, I.H., Miller, J.D., Huo, H.,Okuka, M., Dos Reis, R.M., Loewer, S., Ng, H.H., Keefe, D.L., Goldman, F.D.,Klingelhutz, A.J., Liu, L., Daley, G.Q., 2010. Telomere elongation in inducedpluripotent stem cells from dyskeratosis congenita patients. Nature 464,292–296

Mummery, C., 2011. Induced pluripotent stem cells—a cautionary note. N. Engl. J.Med. 364, 2160–2162

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