Scientists have shown that partial cellular reprogramming can significantly increase the already impressive regenerative capacity of the liver and protect this crucial organ from a potentially lethal injury .
Why can’t we regrow limbs?
Cellular reprogramming induces de-differentiation of somatic cells back into pluripotent stem cells: a ‘factory reset’ that erases cell-specific software and hence cellular identity. In nature, this happens when germ cells are created, but it also occurs in some species during regeneration. For instance, de-differentiation contributes to heart regeneration in zebrafish  and limb regeneration in salamanders , though there is still a lot we do not know about these amazing repair mechanisms.
In mammals, de-differentiation barely happens, and this might be the reason why mammalian tissues are so bad at regeneration. One notable exception is the liver, which has some regenerative capabilities. In this new study, the researchers performed cellular reprogramming in the livers of mice to investigate how this would affect the organ’s regeneration following injury.
Reprogramming without cancer
For their study, the researchers used partial reprogramming, as full reprogramming in vivo is known to induce cancer. Partial reprogramming uses the same reprogramming factors (usually the Yamanaka factors) but induces them for a brief period of time in one or more “pulses”. By balancing the duration of the factors’ expression, it is possible to achieve various degrees of reprogramming (and also some rejuvenation) without taking the cells all the way back to pluripotency.
First, the researchers created a transgenic mouse model that enables liver-specific induction of the Yamanaka factors. Highlighting the dangers of cellular reprogramming in vivo, in the first experiment that induced the factors for 48 hours, all of the mice died of liver failure within days. The problem was solved after the researchers limited the factors’ expression to one day, and in subsequent experiments, the reprogramming treatment seemed to do much more good than harm.
It is hard to pinpoint the exact extent to which a partial reprogramming treatment changes cellular identity. The researchers usually can only tell that some markers associated with differentiated cells get downregulated and that others associated with pluripotency get upregulated, which is what happened in this study as well. The effect, though, appeared to be transient: the pluripotency markers went back to their normal levels after a few days. Importantly, no carcinogenesis was detected in the liver during the 9-month follow-up, showing that the final protocol is safe in this model.
The treatment also boosted the proliferation of hepatocytes, which is required for liver regeneration . Importantly, increased proliferation following de-differentiation is also one of the mechanisms behind limb regrowth in animals.
To determine whether the treatment actually increased regeneration capacity in the liver, the researchers induced lethal chemical liver injury. While all the mice in the control group died two days later, in the group that had received the reprogramming treatment immediately before the injury, half of the mice survived and recovered, showing greatly increased levels of liver regeneration. Unfortunately, reprogramming was not as effective when induced after the injury, although it did improve liver function.
Cellular reprogramming largely remains a black box, as its exact mechanisms haven’t yet been elucidated. Discovering these mechanisms is extremely important, as this must be done before actual reprogramming-based therapies can be devised. In this study, the researchers performed single-cell transcriptomic analysis of both regular and reprogrammed hepatocytes and found that the treatment had significantly upregulated the enzyme topoisomerase2a (Top2a), which is associated with cellular development. Blocking Top2a led to a drastic reduction in reprogramming efficiency and in the mice’s survival following liver injury.
In summary, here, we have developed a mouse model that enables hepatocyte-specific 4F [Yamanaka factors] induction and subsequent lineage tracing of 4F-expressing cells. We demonstrate that liver-specific 4F expression rapidly and transiently induced partial reprogramming and that this enhanced liver regeneration. This study, the first to perform lineage tracing and single-cell transcriptome analyses for 4F-expressing cells in vivo, shows that 4F-mediated cellular partial reprogramming is a potential avenue for inducing a proliferative, plastic progenitor state.
This interesting study shows that partial cellular reprogramming in vivo can greatly increase hepatic regenerative capacity and even protect the liver from otherwise lethal chemical injury without causing cancer. It is also one of the few studies to identify a downstream target of reprogramming. This is an important piece of knowledge about the inner workings of cellular reprogramming, and it might lead to the creation of more safe and effective reprogramming protocols.
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 Hishida, T., Yamamoto, M., Hishida-Nozaki, Y., Shao, C., Huang, L., Wang, C., Shojima, K., Xue, Y., Hang, Y., Shokhirev, M., Memczak, S., Sahu, S. K., Hatanaka, F., Ros, R. R., Maxwell, M. B., Chavez, J., Shao, Y., Liao, H. K., Martinez-Redondo, P., Guillen-Guillen, I., … Izpisua Belmonte, J. C. (2022). In vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell reports, 39(4), 110730.
 Jopling, C., Sleep, E., Raya, M., Martí, M., Raya, A., & Belmonte, J. C. I. (2010). Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature, 464(7288), 606-609.
 Wang, H., & Simon, A. (2016). Skeletal muscle dedifferentiation during salamander limb regeneration. Current Opinion in Genetics & Development, 40, 108-112.
 Ozaki, M. (2020, April). Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. In Seminars in cell & developmental biology (Vol. 100, pp. 62-73). Academic Press.