Spontaneous regaining of pluripotency by iPS cell-derived progeny

by Alexey Bersenev on June 10, 2014 · 0 comments

in embryonic/iPS

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We all know that the absence of undifferentiated residual pluripotent cells can provide a safety of iPS cell-based therapeutic products. However, the safety profile of iPS cell-derived differentiated progenitors and mature cells still under investigation. Considerably, they are safe – no pluripotent cells = no tumors. But not everything is so simple. Recently, Korean researchers described a phenomenon of spontaneous conversion of iPS cell-derived progenitors into pluripotent cells.

The authors observed spontaneous dedifferentiation to pluripotency of iPS cell-derived neural progenitors in culture. I’d like to highlight a few things from this study:

  1. Authors exclude contamination of well established neural stem cell (NSC) lines by pluripotent cells;
  2. Reversion to pluripotent state of some NSC lines happened spontaneously after ~ 4 weeks and 8-9 passages in culture;
  3. Pluripotency marker Oct-4 was detected only after 4-day culture in ES-like media – appropriate culture conditions required for regaining of pluripotency;
  4. Terminally differentiated neurons did not regain pluripotency – this phenomenon attributed only to NSC (iPS-derived stem/ progenitor cells);
  5. Regaining of pluripotency was caused by reactivation of retroviral transgenes (they use 4 Yamanaka’s factor in retrovirus);
  6. Reactivation of endogenous pluripotency genes was secondary to reactivation of silenced exogenous genes (transgenes).

What can we learn from this study? Well, we now have to exclude a possibility of potential spontaneous regaining of pluripotency in iPS cell-derived therapeutic products. Many of such products in development are containing intermediate progeny (stem/ progenitors cells) alone or with a mix of terminally differentiated mature cells. So, how can we test this potentially dangerous phenomenon? How can we guarantee the safety of iPS cell-derived progenitors?

The first and simple thing to do – do not use viruses (especially retroviruses) as delivery system for pluripotency factors. Use virus-free, footprint-free systems. The second thing to do – include residual transgene detection and residual pluripotent cell assays in your quality control tests before release a product.

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