Targeting Mitochondria To Boost Reprogramming

The efficiency of cellular reprogramming gets a boost from an unexpected source: the mitochondria.

AsianScientist (Aug. 18, 2015) – Scientists have discovered two oocyte-enhanced proteins that can enhance cellular reprogramming. Their results, published in Cell Reports, further our understanding of how cellular metabolism changes during aging and during rejuvenation after egg fertilization.

When a sperm fertilizes an egg to create a baby, two adult cells combine to form a new embryo. Artificially combining an egg’s cytoplasm with an adult cell nucleus can mimic this process, reprogramming the adult cell to an embryo-like state. Similarly, induced pluripotent stem (iPS) cells can be reprogrammed from any somatic cell using a cocktail of transcription factors, and can do so without the use of human oocytes which are difficult to obtain.

Unfortunately, oocyte-based reprogramming is still deemed superior in terms of being able to achieve better reprogramming efficiency. Stem cell researchers have long known that the egg cytoplasm contains some special factors that can facilitate cell reprogramming, but their precise identity remained unanswered.

The present study by researchers from the Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR) suggests that old mitochondria—the oxygen-consuming power engines in cells—are roadblocks to cellular rejuvenation.

The GIS team led by Drs. Khaw Swea-Ling, Lim Bing and Ng Shyh-Chang combined oocyte factors with the iPS reprogramming system. Their bioinformatics-driven screening efforts led to two genes: Tcl1 and its cousin Tcl1b1.

By tuning up Tcl1, which is highly abundant in eggs, the researchers were able to suppress old mitochondria to enhance cell reprogramming. They found that Tcl1 does its job by suppressing the mitochondrial enzyme polynucleotide phosphorylase (PnPase), thereby inhibiting mitochondrial growth and metabolism.

“Nobody would have thought that the key to the oocyte’s reprogramming powers would be a mitochondrial enzyme. The stem cell field’s conventional wisdom suggests that it should have been some other signalling genes instead,” said corresponding author of the research, Ng.

These new insights could boost efficacy of the alternative, non-oocyte-based techniques for stem cell banking, organ and tissue regeneration, as well as further our understanding of how cellular metabolism rejuvenates after egg-sperm fertilization.

The article can be found at: Khaw et al. (2015) Oocyte Factors Suppress Mitochondrial Polynucleotide Phosphorylase to Remodel the Metabolome and Enhance Reprogramming.

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Source: A*STAR.
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