ipSCs: the regenerative medicine of the future

A promising form of 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 the possibilities of such developments for the treatment of aging-related diseases. In short, what makes ipSCs the future hope for regenerative medicine.

ipSCs regenerative medicine
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

Back to the beginning

For a while already stem cell therapy has become the “fashion” among scientist and the general public alike, specially for the enormous clinical potential it entails. With the birth 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. In short, stem cells are undifferentiated cells with the potential of turning into whichever cell type of the organism necessary. That’s 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 Yamanaka and his team found it possible to reprogram cells, that is, transform fibroblasts (adult cells, with a defined identity) back into pluripotent stem cells (ipSC) by the use of 4 transcription factors, and with it 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.

Problems with the technology

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. To avoid this, one approach would be to induce ipSCs’ differentiation right 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.

Use in aging

Since at the cellular level aging implicates a decline of stem cell production and a stable arrest of cell cycle and the accumulation of genetic abnormalities, it would be logical to expect that cell reprogramming would not be so efficient in aged cells. ANd though there are reports on this direction, other researches have found no issues to reprogramming potential in senescent cells from old people. 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.

ipSC regenerative medicine
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 as regenerative medicine hold 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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