Pluripotency describes the potential of a stem cell to differentiate into any cell type in the body. Embryonic stem cells derived from the early pre-implantation embryo are pluripotent as well as their engineered counterparts, iPSCs (induced pluripotent stem cells). Many labs have focused on understanding the gene regulatory networks maintaining pluripotency. This knowledge allowed Kazutoshi Takahashi and Shinya Yamanaka to create iPSCs by converting an adult cell back to a pluripotent state.
iPSC technology revolutionized the way we think about stem cell biology and regenerative medicine. They allow us to study diseases in a dish and provide us with the potential for personalized regenerative medicine. For this reason, Yamanaka and Takahashi have received many awards. Last year at the annual ISSCR meeting, Yamanaka and Takahashi together received the McEwen Award for Innovation.
While Yamanaka has received worldwide attention (and mumblings of Nobel prize potential), he has received particular attention in his home country, Japan. Japan has invested over $15 billion to support iPSC technology research and my Japanese friends tell me that ‘Shinya Yamanaka’ and ‘iPSC’ are household terms. As a testament of Japan’s excitement and support of stem cell research, the emperor and empress came to celebrate the 10th annual ISSCR meeting in Yokohama, Japan earlier this month.
At the meeting, Takahashi opened his talk by reminding us of his brief words last year during his acceptance of the McEwen Innovation award, “hard to know why I am here, I only did transfections,” referring to the experimental technique used to generate iPSCs. He joked that his speaker time went up by 30-fold as he was given a plenary talk, providing him 30 minutes to tell us about his current work. Takahashi performed a large-scale comparison of 75 ESC lines and 163 iPSC lines and found that 5% of ESC/iPSC lines performed poorly in differentiation assays. He can distinguish good performing lines based on epigenetic status of a panel of genes (we will have to wait for publication to find out which genes are included in the panel).
Rudolf Jaenisch was awarded the McEwen Award for Innovation this year, for his contribution to the iPSC field. In his talk, he addressed two issues in which the field continues to struggle with six years after the first iPSC report. 1) The Jaenisch laboratory identified outer pluripotency circuitry members as markers capable of distinguishing true iPSCs and 2) he used isogenic control lines for disease modeling applications of iPSCs to control for genetic differences that may cause cells to behave differently independent of disease.
While many talks focused on the gene networks regulating pluripotency, Austin Smith discussed the upstream signaling factors that maintain the pluripotent state. He showed us that the pluripotency network can be rebuilt in germ cells by changing their signaling environment. Smith hopes that this could be translated to adult cell types one day for the generation of iPSCs, providing a method of iPSC generation that does not require genetic manipulation, but admits that this will likely be very difficult.
Recap of experimental findings presented:
- A small portion of iPSC lines have a block in differentiation ability. Lines with good differentiation ability can be identified by molecular markers (markers TBA).
- The pluripotency network can be rebuilt in adult cells by over-expressing outer circuitry members (Esrrb, Sall4, Lin28 and Nanog) in the absence of Yamanaka factors.
- Isogenic controls should be used for disease modeling in iPSCs. Disease relevant gene defects can be corrected using zinger finger nucleases or TALEN technologies.
- Primordial germ cells can be reprogrammed into iPSCs without genetic manipulation by changing the signaling environment (culturing cells in 2i + LIF).
All of these findings contribute to the understanding of how pluripotency is regulated in stem cells, how pluripotency can be restored in differentiated cell types and how we can enhance iPSC generation and application. This knowledge is essential for the advancement of iPSC technology towards drug discovery and clinical applications.
Angela C. H. McDonald
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