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May 15, 2013

A First: hESCs Generated from Somatic Cells

  • Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by way of somatic cell nuclear transfer (SCNT) has for years seemed no more than a pipe dream in the field of regenerative medicine.

    But today, scientists report having for the first time generated patient-matched ESCs following SCNT. Writing in Cell, Oregon Health & Science University’s Shoukhrat Mitalipov, Ph.D., and his colleagues present a modified SCNT protocol that supports the reprogramming of human somatic cells to the embryonic state.

    “We report a pretty efficient technique that allows deriving of embryonic stem cells,” Dr. Mitalipov told reporters during a press briefing. Additionally, “we show the battery of tests that show these cells are now off the initial somatic cell gene expression and now they look like embryonic stem cells,” he said.

    While Dr. Mitalipov and his colleagues had previously demonstrated that SCNT procedures could be used to reprogram rhesus macaque adult cells into their embryonic counterparts, several factors—including a premature exit of oocytes from meiosis—prevented the team from achieving the same result with human cells. By systematically interrogating how oocyte factors are reprogrammed, the team eventually identified ways in which it might optimize the protocol.

    Using skin fibroblast cells from a young male patient and human MII oocytes from healthy donors, the team applied its modified approach, eventually generating four ESC lines. Next, the researchers confirmed that the ESCs they’d created could in fact differentiate into any cell type, and inherited their nuclear genomic content exclusively from the nuclear donor fibroblasts with no detectable contribution of oocyte alleles. A defining feature of SCNT, they noted, is that the mtDNA in resulting ESCs is largely contributed by the oocyte.

    Beyond traditionally derived ESCs and induced pluripotent stem cells (iPSCs), “we are adding a new class of pluripotent stem cells, also patient-derived,” Dr. Mitalipov said. But, he added, NT-ESCs such as those his team have generated could offer researchers significant benefits over other approaches.

    “If the initial donor cell has mitochondrial dysfunction, specifically caused by mutations in mitochondrial DNA, somatic cell nuclear transfer allows replacement of this mitochondrial component because during nuclear transfer, we use a cytoplasmic or mitochondrial genome that comes from the egg,” he said. “So the embryonic stem cells developed this way will have completely the mitochondrial function restored.”

    Dr. Mitalipov stressed that like all hESC lines, NT-ESCs remain in research mode. But he said that comparative research could be key to fueling potential clinical applications down the road.

    “Now we have a new way of creating these stem cells. Hopefully, by comparing the SCNT-derived cells to iPS cells and to genuine embryonic stem cells derived from fertilized embryos, now we can probably tell the differences or similarities and hopefully choose the best cell for future therapeutics applications,” he said. “Since we have opened up the technology, hopefully the technique can be perfected. Just like with iPS cells, the initial results were encouraging, but very inefficient. But now, it’s such an efficient way. So hopefully, the SCNT approach will also be perfected by different labs contributing to this field.”

    Meanwhile, Dr. Mitalipov and his colleagues hope to further test the limits of their technique, applying it in attempts to reprogram a variety of somatic cells. “So far we tested with patient cells derived from a young boy, but we would like to test if age of the somatic cell does matter, so we would like to derive from a variety of . . . patient cells,” he said. The researchers would also like to further optimize their protocol, making it more amenable to scaling. “Hopefully we can make it so efficient that you would maybe only need one egg, or maybe even half an egg, to make one cell line,” Dr. Mitalipov said.

    The study, “Human embryonic stem cells derived by somatic cell nuclear transfer” appeared online in Cell May 15.


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