Reprogramming of ordinary somatic cells into induced pluripotent stem cells (iPSCs) capable of generating any cell type is very much a going concern these days. The first cell therapies based on the transplantation of patient-matched cells derived from iPSCs are entering trials. More recently, however, researchers have been experimenting with the more radical idea of reprogramming cells in situ, in tissues. At first glance (and later consideration) this seems enormously risky, a fast path to cancer. Yet in mouse studies it appears, at least initially, to be quite beneficial. It will take a great deal more data to overcome skepticism about the cancer risk, but it seems there is a faction of researchers ready to work towards that goal.
Equally intriguing is the evidence for reprogramming to reset some of the markers of cell and tissue age, such as mitochondrial dysfunction. A complete catalog of what is fixed and what is not fixed by this process, and which of those items are more or less important than the others, has yet to be assembled. This is a comparatively recent development in the field, and, accordingly, comparatively little exploration has taken place. Will reversal of aspects of aging hold up when cells are put back into tissue? Which of the changes are lasting versus transient? A great deal of work lies ahead.
To our knowledge, the first study reporting cell rejuvenation was published in 2011. It was known that cells from old individuals display a typical transcriptional signature, different from that of young counterparts. It was also known that fibroblasts from old donors have shortened telomeres as well as dysfunctional mitochondria and higher levels of oxidative stress. The researchers first explored the effect of cell reprogramming on the above features. In order to efficiently reprogram fibroblasts from healthy centenarians and very old donors, the authors added the pluripotency genes NANOG and LIN28 to the Yamanaka OSKM reprogramming cocktail. This six-factor combination efficiently reprogrammed fibroblasts from very old donors into typical induced pluripotent stem cells (iPSCs).
These blastocyst-like cells showed a higher population-doubling (PD) potential than the cells of origin as well as elongated telomeres and a youthful mitochondrial metabolism (estimated by measuring mitochondrial transmembrane potential and clustering transcriptome subsets involved in mitochondrial metabolism). Using an appropriate differentiation cocktail, the iPSCs were differentiated back to fibroblasts, whose transcriptional profile, mitochondrial metabolism, oxidative stress levels, telomere length, and PD potential were indistinguishable from those of fibroblasts from young counterparts. Taken together, the data revealed that the cells had been rejuvenated.
Until late 2016, it was believed that although cells taken from old individuals could be fully rejuvenated, rejuvenation in vivo was not possible as a continuous expression of the Yamanaka OSKM genes in animals had been shown to cause multiple teratomas. However, then it was reported for the first time that cells and organs can be rejuvenated in vivo. The authors used transgenic progeric mice. After 6 weeks of partial reprogramming cycles, the experimenters could observe some improvements in the external appearance of experimental mice, including a reduction in spine curvature as compared with untreated counterparts (controls).
A subgroup of the experimental and control mice was sacrificed and some of their tissues and organs analyzed (skin, kidneys, stomach, and spleen). Controls showed a variety of alterations at an anatomical and histological level in the above organs whereas some of these aging signs disappeared or were attenuated in the experimental mice. Some aging signs remained unchanged by the treatment. Furthermore, although the experimental animals kept aging, they showed a 50% increase in mean survival time as compared with wild-type progeric controls. If the treatment was interrupted, the aging signs came back.