Editors' ChoiceStem Cells

Surprise After the Prize: Innate Immune Signaling Required for Pluripotency

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Science Translational Medicine  05 Dec 2012:
Vol. 4, Issue 163, pp. 163ec220
DOI: 10.1126/scitranslmed.3005422

Induced pluripotent stem (iPS) cells—which can be made from differentiated cells such as fibroblasts—are big news, leading to this year’s Nobel prize for Yamanaka and Gurdon, who discovered that mature cells can be reprogrammed to become pluripotent. The hope is that exposure of mature cells to four key transcriptional factors (Oct4, Sox2, Klf4, and c-Myc), which reverses differentiation to yield stem cells, can produce cells needed for repair of damaged tissues—myocytes, neurons, or insulin-producing β cells, for example. Use of iPS cells would circumvent the ethical problems arising from fetus-derived embryonic stem cells and alleviate concerns about immune reactions because iPS cells could be derived from a patient’s own fibroblasts. Nevertheless, for translation into the clinic, major hurdles have to be overcome first, including efficient and safe delivery of the key factors. Lee and colleagues now report a surprising facilitator of reprogramming: signaling through Toll-like receptor 3 (TLR3), a serendipitous effect of the retrovirus carrying the reprogramming factors into the cell.

So far, to switch mature cells to iPS cells, the factors have been overexpressed after delivery via a retroviral vector, a technology not ideal for clinical use as foreign DNA becomes integrated into the genome. While looking for alternatives, Lee et al. stumbled upon a previously unknown fact: The retrovirus is not just a delivery vehicle for the transcriptional factors. Rather, it also activates innate immune pathways, which turn out to be critical for cellular reprogramming. The authors show that signaling through TLR3 is a key step for reprogramming the cells, required for altering expression of epigenetic modifiers. TLR4 signaling reduces HDAC1, changing the methylation status of the promotors of Oct4 and Sox2 and leading to an open chromatin state for the pluripotency genes. Knockdown of TLR3 inhibited pluripotency gene expression and generation of iPS cells. When the authors replaced the retrovirus with a synthetic ligand of TLR3, polyinosinic polycytidylic acid, and provided the key factors as cell permeant proteins, iPS cells could be efficiently induced.

These findings have implications beyond the generation of iPS with virus-free systems because they imply that innate immune signaling—and inflammation in general—alters the epigenetic state of cells, enhancing plasticity of TLR3-expressing cells in the presence of pathogens.

J. Lee et al., Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151, 547–558. [Abstract]

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